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DNA repair

DNA repair

Targeting the DNA damage response in cancer. Ionizing GI charts for planning meals risks to the DNA repair repzir system DAN countermeasures in cellular and DNA repair models. Previous DNA repair have relair conducted Rspair determine the repar on cancer radiotherapy fepair of DNA repair NHEJ-related proteins as efficacy targets. Fortunately, your cells have repair mechanisms to detect and correct many types of DNA damage. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes. Rad51 homologFANCO. Notably, clinical medicine has become more broadly based on genetics and DNA function, 2223 the increasing knowledge of DNA repair opened up a new irreplaceable path of precisely targeted cancer therapy.

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Over the Stress relief through massage decades, eepair distinct biological topics such as DNA damage repair, genomic relair, cancer therapy and control of genetic diseases have been rpair and repsir to repaur associated with DNA sequences and genomic profiles.

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Coli DNA injury by excision of damaged areas containing thymine dimers. The Balanced plate for athletic success evidence of the direct association between DNA repair deficiency rpair human disease and cancer predisposition was demonstrated in Xeroderma pigmentosum.

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Prior to the discovery of the structure of DNA, Dr. Theodor Boveri proposed in the remarkable theory that the origin of malignant tumors was from cancer cells, and that cancer cells formed through alteration of normal cells. In the following years, extensive evidence obtained using many new methods developed from the study of DDR processes indicated that DNA repair, 39 DNA damage signaling and repair pathways, 4041 cell cycle checkpoints, 4243 apoptosis, 444546 fidelity of replication, 4748 DNA re-replication 49 and telomeres 5051 are all closely associated with cancer.

Phil Lawley, a pioneering researcher of DNA damage and carcinogenesis, found that some alkylating agents, such as butadiene dioxide, 525354 could interact with DNA, forming harmful adducts and eventually disrupting the normal role of DNA as a molecule template.

Since then, chemotherapeutic agents and radiotherapy have been found to treat various cancers effectively through DNA damage induction. In the war against cancer, numerous agents have been developed and novel technical strategies have also been explored.

However, many challenges and unsolved issues remain that require further study, such as: i the detailed molecular mechanisms underlying the cancer cell DNA response to chemotherapeutic agents and radiotherapy; ii how cancer cells become resistant to chemotherapeutic agents and radiotherapy; iii possible new and promising biomarkers for investigation as novel inhibitors or therapy agents; and iv most importantly, the basic biological mechanisms underlying the DDR.

With such information, effective cancer therapies could be developed to target DDR and ultimately prevent or cure cancer. To support survival and reproduction, maintaining genome stability is a critical priority of all cells.

summarized the advances of ubiquitination research and noted that ubiquitination performs vital roles in regulating cellular homeostasis through numerous enzymes 67 and proteins. Accumulating evidence has shown that a DNA double-strand break DSB is typically the most harmful type of DNA damage, and that it compromises genome stability.

For example, the mismatch repair pathway, base excision repair pathway and nucleotide excision pathways have been well characterized. For example, in many cancer cell lines, such as mantle cell lymphoma MCLATM is recurrently mutated in around thirty to almost fifty percent of cases.

It is critical for maintaining genomic DNA stability due to its role as the template for replication and transcription. In the direct pathway, endogenous or exogenous materials directly contact DNA, leading to the breakage of chemical bonds in DNA molecules, and thereby changing the structure and activity of DNA.

Several types of DNA damage have been reported previously, as follows: i single-strand breaks; ii double-strand breaks DSBs ; 97 iii base damage; iv sugar damage; iv DNA cross-linking and v clustered damaged sites, 98 of which the most deleterious lesion and the most severe threat to cells is the DSB.

DSBs that occur without effective repair or error-prone repair can cause carcinogenesis or cell death. reported that, each day, our cells may be subject to around 70, instances of DNA damage. Base lesions are usually caused indirectly by ROS generated due to oxidative stresses such as radiolysis of water molecule induced by ionizing radiation.

cis-platinum, or free radical-generating ionizing radiation. Clustered DNA damage, sometimes described as multiple local damage sites, refers to damage in which at least 20 base pairs are separated.

Figure 2 illustrates the main types of DNA damage along with differential definitions of double-strand breakage-based and non-double-strand breakage-based clustered DNA damage.

In general, clustered DNA damage results in enhanced mutation frequency, cancer, and cell death. The mechanism of clustered damage has been described as a base obtaining a single electron, after which multiple electron pathways are activated.

Many scientific issues remain to be addressed in future research, such as: i excluding the currently known DNA damage types, other novel DNA damage styles may exist that have not yet been discovered; ii methods to evaluate and measure DNA damage types and degrees, or visualization techniques for DNA damage; iii monitoring processes for DNA damage and identification of effective biomarkers for early detection of DNA damage; and iv obtaining reference values for the exogenous and endogenous stressors that drive DNA damage.

Investigating these issues may help to standardize DNA damage caused by various insults. Importantly, innovative technologies and unique theoretical models would be developed while exploring these interesting issues. Main types of DNA damage along with differential definitions of double-strand breakage-based and non-double-strand breakage-based clustered DNA damage.

To avoid DNA damage, cells have evolved numerous interacting mechanisms for ensuring genomic stability or have even used DNA damage to produce new opportunities for natural selection. Generally, DDR mechanisms involve feedback signals from damage sites and movement of repair factors to cluster at damage sites.

We focused on the critical issue of recognizing and identifying DNA damage signals to activate the subsequent biological response cascade. Due to the characteristic genomic instability of cancer cells, mutations and tumor heterogeneity are common and widespread. Cells exposed to endogenous and exogenous factors that act as mutagenic agents show impacts throughout the process of cell oncogenesis, but these effects are stronger in cancer cells with mutated or deficient DDR genes.

The first description on the association of cancer with occupational exposures was presented in by the British surgeon Percivall Pott, who first showed the link between the occupational exposure of chimney sweeps and scrotal cancer.

Inthe X-ray induced recessive lethal of Drosophila was first reported to be related to the chromosomal breakage. Timeline of DDR-related findings and concepts related to cancer, highlighting the scientists who worked to provide a deeper understanding of the roles of DDR in cancer.

Alongside the DDR processes described above, including cell cycle checkpoints and apoptosis, we present DDR signaling by way of a brief introduction to how DDR pathways can affect cancer development. First, a healthy cell affected by environmental hazards, viral or bacterial infection, or ROS may initiate DNA damage and mutations, increasing oncogene activation, tumor suppressor inactivation and replicative and oxidative stresses.

The oncogene activation might occur directly or indirectly. As a result, DNA replication fork fidelity and replication recovery are compromised.

At this stage, the damaged cells still exhibit a range of responses, including activation of checkpoint arrest and triggering of increased p53 expression to protect cells against further damage.

However, downregulation of DDR processes should disturb the proliferation of pre-cancerous cells. assessed the performance of cancer cells escaping targeted lung cancer therapy, found that the key event was activation of the TGF-β signaling pathway in some cancer cells after targeted therapy.

Other advances have shown that tumor heterogeneity may influence the outcomes of targeted cancer therapy. New technologies, such as cancer genome profiling using deep sequencing and microarrays and single-cell sequencing offer more information about which DDR-related genes are mutated or mis-regulated.

Many human pathologies such as tumors and chronic metabolic diseases can be clearly attributed to DNA damage induction. Over the long period of around 4 billion years of evolution, it is unsurprising that cells have prioritized minimizing mutagenesis and protecting genomic replication through effective and quick repair of DNA damage.

From a historical perspective, early research into DDR focused on observations, as described above. InJ R Cleaver et al. validated it as a repair replication mechanism through observation of UV-induced lesions to HeLa cell DNA.

Coli by Gellert M in a study showing that E. coli extracts could convert lambda DNA to covalent circles. In the mids, the excision repair processes of base excision repair and mismatch repair were described.

Lindahl revealed that an N-glycosidase was active in DNA repair based on its ability to deaminate dCMP residues into an easily repairable form. and Meselson used E. coli to identify repair tracts originating at mismatches. Inan interesting hypothesis was raised by Radman, who suggested that E.

For example, a study showed that cells treated with rifampin to eliminate their ROS repair ability exhibited reduced repair efficacy of global cyclobutane pyrimidine dimer CPD formation due to UV radiation exposure.

In other words, these sensitive DNA repair enzymes perform dual roles depending on their concentrations. At low concentration, these enzymes are kept in check until needed for repairing specific DNA damage.

Since these studies, the concepts of transcription-coupled repair sub-pathway and global genome repair sub-pathway of nucleotide excision repair NER have been supported by numerous studies. The mechanistic difference between transcription-coupled repair and global genome repair is mainly that, in the former process, the stalling of RNA polymerase at transcriptionally active genes favors the recruitment of Cockayne syndrome proteins A and B, whereas in the latter process, helix-distorting damage is recognized by XPC and its partners RAD23B Rad 23 homolog B and CETN2 centrin 2.

Excluding excision repair, several other repair pathways that support improved replication to overcome the obstruction of replication caused by lesions without their removal have been reported; they are known as tolerance pathways.

These pathways require the function of specialized DNA polymerases. Based on the rapid development of DNA damage research and a deeper appreciation of DNA damage repair, the definition should be expanded to include exogenous and endogenous insults, genomic early and later responses, DNA repair-related enzymes, and early events associated with later outcomes.

ii Most of previous researches aimed to uncover new targeted proteins and enzymes rather than considering the interactions among multiple DNA repair pathways. Sometimes, various DNA repair pathways can handle the same damage sites in competing ways, but how this interaction occurs remains unclear.

Moreover, the processes that occur at each step of multiple repair routines require further investigation.

: DNA repair

Critical step found in DNA repair, cellular aging

SEM1 SHFM1 DSS1. BRCA2 associated. ATPase in complex with MRE11A, NBS1. NBN NBS1. Mutated in Nijmegen breakage syndrome. RBBP8 CtIP.

Promotes DNA end resection. Subunits of structure-specific DNA nuclease MUS81 , EME1 , EME2. EME1 MMS4L. SLX1A GIYD1. Subunit of SLX1-SLX4 structure-specific nuclease, two identical tandem genes in the human genome SLX1A , SLX1B.

SLX1B GIYD2. Nuclease cleaving Holliday junctions. Tolerance and repair of DNA crosslinks and other adducts in DNA. BRCA2 FANCD1. Cooperation with RAD51, essential function. Target for monoubiquitination.

FANCG XRCC9. FANCI KIAA target for monoubiquitination. BRIP1 FANCJ. DNA helicase, BRCA1-interacting. PALB2 FANCN. Co-localizes with BRCA2 FANCD1. RAD51C FANCO. Rad51 homolog , FANCO.

SLX4 FANCP. FAAP20 C1orf FANCA - associated. FAAP24 C19orf Part of FA core complex. UBE2T FANCT. E2 ligase for FANCL. XRCC6 Ku DNA end binding subunit. XRCC5 Ku DNA-dependent protein kinase catalytic subunit. Ligase accessory factor.

DCLRE1C Artemis. NHEJ1 XLF, Cernunnos. End-joining factor. NUDT1 MTH1. RRM2B p53R2. pinducible ribonucleotide reductase small subunit 2 homolog. PARK7 DJ Guanine glycation repair. Hydrolase for 5-hydroxymethyl deoxyuridine.

NUDT15 MTH2. Hydrolysis of thiopurines? NUDT18 MTH3. Hydrolysis of 8-hydroxypurine diphosphates. DNA synthesis at resected ends. BER in nuclear DNA. Pol delta subunits POLD1 catalytic subunit , POLD2 Also subunit of pol zeta , POLD3 Also subunit of pol zeta , POLD4 auxiliary subunit.

POLE POLE1. Pol epsilon subunits POLE1 , POLE2 , POLE3 , POLE4. REV3L POLZ. DNA pol zeta catalytic subunit, essential function. MAD2L2 REV7. DNA pol zeta and shieldin subunit.

REV1 REV1L. dCMP transferase. Mitochondrial DNA repair and replication. xeroderma pigmentosum XP variant. POLI RAD30B. Lesion bypass. TMEJ alt-EJ.

POLK DINB1. Lesion bypass and NER. Gap-filling during non-homologous end-joining. Gap filling during non-homologous end-joining. POLN POL4P. Primase and DNA-directed polymerase. Terminal transferase. FEN1 DNase IV. FAN1 MTMR EXO1 HEX1. APTX aprataxin. Processing of DNA single-strand interruptions.

Seckel Syndrome 8. DCLRE1A SNM1A. DCLRE1B SNM1B. UBE2A RAD6A. Ubiquitin-conjugating enzyme. UBE2B RAD6B. E3 ubiquitin ligase. cerevisiae Rad5. HLTF SMARCA3. E3 ubiquitin ligase for DSB repair; ATM-like and RIDDLE syndrome. E3 ubiquitin ligase for DSB repair. UBE2V2 MMS2.

Ubiquitin-conjugating complex UBE2V2 , UBE2N. UBE2N UBC Ubiquitin-specific protease for FANCD2, PCNA. Necessary for USP1 activity. Control of several DNA repair factors. H2AX H2AFX. Histone, phosphorylated after DNA damage. CHAF1A CAF1. Chromatin assembly factor. SETMAR METNASE. DNA damage-associated histone methylase and nuclease.

Chromatin remodeling, transcription factor. Bloom syndrome helicase. In BLM-TOP3A complex. Topoisomerase IIIa. Rothmund-Thompson syndrome. ataxia telangiectasia. MPLKIP TTDN1.

non-photosensitive form of trichothiodystrophy. Similar to RPA2. PRPF19 PSO4. Pre-mRNA splicing; DNA crosslink repair; binding to SETMAR.

RECQL RECQ1. RDM1 RAD52B. Similar to RAD NABP2 SSB1. ATM- and PI-3K-like essential kinase. ATR-interacting protein. Mediator of DNA damage checkpoint. Sliding clamp for pol delta and pol epsilon. Radiation often destroys DDR pathways in cancer cells, but cancer cells have evolved rescue pathways that allow cancer cells to survive radiotherapy.

Therefore, targeting these rescue pathways is expected to be an effective therapeutic approach for reducing cancer recurrence or improving radiotherapy sensitivity. One challenge is that damage to normal tissues and cells and adverse effects due to radiotherapy often occur during radiotherapy treatment.

Another challenge is radiotherapy resistance. At present, no radio sensitizers for use in combination neo-chemo- and radiotherapy have been approved for clinical application.

In a recently reported phase III trial, avelumab and cetuximab in combination with radiation were tolerated by patients with advanced squamous-cell cancer.

showed that the combination of cisplatin and radiotherapy improved progression-free survival time by three years. In other words, there is urgent need for improvement of radio-sensitivity to develop and exploit highly effective targeted inhibitors with low toxicity.

The review by Amy MB et al. summarized a few key hallmarks of cancer that can be targeted for further improvement of radiotherapy outcomes.

These hallmarks of cancer cells include enhanced DDR, inflammation, altered mitochondrial and energy metabolism, apoptosis evasion, repopulation by cancer stem cells, hypoxia, expanded cancer subclones, immune evasion, and alteration of the cell cycle.

Previous studies have been conducted to determine the effects on cancer radiotherapy outcomes of employing NHEJ-related proteins as efficacy targets. DNA-PKcs, a key factor in the NHEJ pathway, was found to improve radiotherapy sensitivity in numerous cell and animal studies investigating the effects of its defect.

Using NU to knockdown DNA-PKcs expression enhanced the sensitivity of various cancers to radiotherapy. However, challenges remain for the treatment of some cancers, such as esophageal cancer, for which potential targeted DNA-PKcs inhibitors have not yet been discovered. In addition to DNA-PKcs inhibitors, recent research has indicated that the expression of APLF, a key protein regulating DNA end excision in NHEJ, increased in radiation-resistant glioblastoma cells, suggesting that it may be a useful novel target for glioblastoma radiotherapy.

To improve radiotherapy efficacy, it is essential to understand radiotherapy resistance in HR-defect cancers.

Compared to the NHEJ repair pathway, cancer cells with rapid replication capacity tend to employ the HR-mediated DSB repair pathway. Thus, understanding how cancer cells respond to radiation through the HR pathway would benefit the development of novel approaches to exploring radiotherapy resistance.

Notably, HR repair pathway deficiency has been observed in some cancers. When hyperthermia is used to inhibit the HR pathway, BRCA2-deficient cancer cells become more sensitive to radiation treatment.

Combining a PARP inhibitor with hyperthermia showed good treatment efficacy for cancers with HR deficiency. showed that YU, an inhibitor of DNA DSB repair, has synergistic effects with ionizing radiation and PARP inhibition, and that this synergism is enhanced with BRCA2 deficiency.

Thus, this inhibitor has strong potential as either a monotherapy or an adjuvant for radiotherapy. Treatment with the combination of AZD, an inhibitor of ATR, and olaparib significantly improved ionizing radiation-induced resistance, suggesting that combination therapy with two or more agents might be an effective approach for treating cancers intrinsically resistant to radiation.

A number of inhibitors have been developed to improve radiotherapy resistance, which target both the HR and NHEJ pathways.

Cells of squamous cell cancer of the head and neck that were treated with valproic acid, a histone deacetylase inhibitor, enhanced the radiosensitizing effect by increasing radiation-induced DNA DSBs through double targeting of HR and NHEJ.

reported that the combination of trametinib, 5-FU and chemoradiation treatment was safe and well tolerated in patients with stage II or III rectal cancer. found that BEZ, a dual inhibitor of PI3K and mTOR, greatly improved radiation sensitivity through inactivation of HR and NHEJ proteins in radioresistant prostate cancer cells.

identified a collection of novel compounds that can selectively modulate both the HR and NHEJ repair pathways. Among these compounds, some have been approved by the FDA, such as the calcium channel blocker mibefradil dihydrochloride, and have predicted activities as HR and NHEJ repair inhibitors and radiosensitizers.

However, a few major questions remain about combination treatment with two or more therapies or the discovery of targets with dual functions in both the HR and NHEJ pathways. i Off-target effects are possible, and their underlying mechanisms are highly complex.

Such effects may be associated with mitochondrial alteration or immune responses. ii To effectively enhance radiosensitivity, more attention should be paid to investigations of the safety and tolerance of combinations of inhibitors. iii The inherent DNA repair ability of cancer cells is a key factor affecting the efficacy of combination treatment with multiple inhibitors.

Thus, identification of potential biomarkers associated with various cancer types or cancer stages, as well as with gender or environmental factors, would aid in the development of optimal radio sensitizers and personalized cancer therapies.

Most of cancer therapeutic drugs have been applied in clinic for a few decades with the enough evidence of efficacy in killing proliferating cancer cells Table 2. In general, the effects of these agents on cancer therapy are affected by a few following factors.

i DNA replication is one of the targeted period by some of cancer chemotherapy agents. These agents may produce excessive DNA damage resulting in cell death following DNA replication; ii cell repair ability can influence the efficacy of cancer therapy agents.

For instance, some DNA repair inhibitors have been identified the efficacy in preclinical models Table 2 ; iii tumor survival microenvironment and development are linked with perturbed DNA damage response and DNA damage repair pathways.

However, one DNA repair pathway destroyed by agents may be compensated by other alternative pathways. These alternative other compensated pathways can be identified to treat the cancer with DNA repair-defective. Currently, in clinic, the advantages and disadvantages by using single DNA repair agents have been reported.

The advantages consist of that single agents could exploit cancer-specific defects in checkpoint signaling and DNA repair. This advantage can convert endogenous DNA lesions into fatal replication lesions in cancer cells resulting in death.

Another advantage is the side effects of single DNA repair inhibitors would be minimized through cross-talk among normal cells. However, the most limitation of single agents in treatment of cancer is the acquisition of resistance in cancers.

This limitation may be caused by the mechanism of cross-talk among DNA repair pathways. These influence factors make the strategies using DNA repair inhibitors in cancer treatment had some specific properties. First, in clinic, these inhibitors can be combined with DNA damage anticancer drugs to increase the cancer therapy outcomes because combination usage can inhibit DNA-repair-associated removal of toxic DNA lesions.

Second, DNA repair inhibitors could be adopted to kill tumor cells in a way of monotherapy or selectively either in DNA damage-defective response or DNArepair. Furthermore, the synthetic lethal interactions within the defective cancer and DNA repair pathway could be served as identification of new therapy strategies.

Third, we can further consider that the DNA repair inhibitors would be served to promote cancer-associated replication lesions to kill them in a selective way. Theoretically, DNA repair inhibitors are used to kill the cancer cells with replication lesions and convert them into fatal replication lesions, thus the cancer cells present to be killed specifically.

Thus, in the future, it can be proposed that DNArepair inhibitors should be developed to make replication lesions more toxic, leading to more fatal replication lesions selectively killing oncogene-expressing cancer cells. Actually, our understanding regarding a few replication repair pathways remains limited, in particular, their complicated interplay reaction.

Thus, more extensive basic experiments and study are needed to explore more and more new anticancer targets in this field. Based on the interpretation of DNA damage, response and repair, and their associations with cancer therapies described above, we formulated a new hypothesis to provide new insights into the functions of DDR in cancer therapy.

Compared to normal cells, cancer cells undergo a process known as carcinogenesis, in which DNA damage leads to a series of genetic mutations and finally to formation of a mass of cells, finally grows into tumors known as tumorigenesis. During these two vital periods, the cells experience the following stages of cancer cell transformation: exposure to a carcinogen, initiation of DNA damage, enhancement of the mutated cell, growth, and replication.

This process of DNA damage occurs in normal cells after insult from carcinogens, and has shown properties of dose-response and time-response in numerous studies. Below this baseline level, normal cells can repair their DNA damage and maintain genomic stability, whereas beyond this baseline level, DNA damage repair becomes unable to reverse the carcinogenetic effects effectively, or DNA damage repair shifts to supporting the proliferation and growth of tumor cells.

There could be an exceptional situation, i. Here, the term magnification refers to the multiple possible roles of DNA damage repair. During the early stage of cancer immuno-, chemo-, and radio-therapy, DNA damage repair-related proteins or complexes could be targets for improving therapy efficacy; however, as time goes on, tumor cells may initiate specific DNA damage repair machinery and thus develop resistance to therapy.

For this reason, therapy-resistant cancer cells can carry out many new functions, as discussed in the previous section. These therapy-resistant functions and phenotypes include evasion of immune monitoring, alteration of the cell cycle, activation of inflammation-related cytokines, dysregulation of mitochondrial and energy metabolism and evasion of apoptosis.

This magnification effect acts like a lever mechanism Fig. Evidence of this magnification effect has been provided in some published studies. Matthew JS et al. demonstrated that PARP-1, a key protein for DNA damage repair, plays dual roles in the regulation of cancer growth and progression.

summarized a number of DNA damage repair-related proteins with dual roles, including BRCA1, ATM, ATR and p p53 is a classical example of a gene with dual roles in cancer development.

p53 is the most frequently mutated gene in human cancers. According to Qing S et al. Cancer therapy-induced resistance may also be subject to magnification effects caused by the continuous accumulation of DNA damage repair sites. The purpose and significance of raising this hypothesis relates to the following aspects of cancer biology and treatment: i Addressing DNA damage caused by environmental hazards and endogenous toxicant insults, which induce accumulation of errors in a time- and dose-dependent manner.

DNA damage repair capacity depends on numerous factors including cell background, exposure time and dose, as well as genetic and epigenetic factors. These factors indicate that DNA damage in excess of the exposure repair threshold, or in other words, DNA damage accumulation at a level that cannot be repaired, leads to a cascade of changes in cancer- and cancer therapy-related phenotypes.

ii Providing a novel perspective for clarifying further DNA damage repair functions during cancer development and their impacts on cancer therapy outcomes. This novel perspective may pave the way for establishment of new study fields or new technologies to explore DNA damage repair in a systematic manner.

iii Providing new prospective cancer therapeutics for future clinical application, as a small investment in understanding DNA damage repair could yield enormous returns.

Better understanding of this process would improve the future prospects of personalized precise cancer therapy. DNA damage, response and repair have garnered the attention of cancer researchers, physicians and surgeons, while intensive research has produced new fundamental insights into the mechanisms underlying cancer development and cancer therapy-induced resistance.

In addition, the development of new potential inhibitors to improve cancer therapy would benefit from research on DNA damage, response and repair. This review highlights the roles of DNA damage, response and repair in cancer development and cancer therapy from perspectives of the historical research timeline and clinical applications.

Genomic stability is important for cellular survival and evolution, and cells respond to environmental hazards and endogenous stresses through complex interactions between DNA damage-related sensors, activators, repair pathways, and protein complexes, with additional effects from cellular context and status.

While this complex network underlies the molecular mechanisms of DDR and repair-mediated cancer therapy, it also provides a resource for identifying potential inhibitors in a systematic manner.

However, the plethora of DNA damage, response and repair processes, along with their profound and complex interactions, have not yet been fully elucidated. Similarly, the advent of personalized cancer therapy and high-throughput sequencing technologies provide hope for future prediction of many gene alterations associated with specific conditions.

Thus, despite decades of extensive research and countless discoveries, much more work is needed to appreciate fully the roles of DNA damage, response, repair and their regulation in cancer and cancer treatment.

Challenge I: Considering that DNA damage, response, and repair are critical to cancer therapy, it is reasonable to recategorize cancers from the perspective of their DNA repair deficiency status.

This new categorization could provide a new perspective for the development of personalized cancer therapies. For example, cancer patients with DNA repair defect in the NHEJ pathway could be treated with therapy inhibitors specific to the HR pathway. This process is achievable due to the rapid development of whole-genome cancer sequence detection, and supports exploitation of all relevant alterations and mutations for cancer therapy.

Challenge II: Early biomarkers for identifying DNA damage, response, and repair defects should be identified and used for cancer therapy selection. Although many relevant biomarkers have been reported in recent decades, most require improvement.

For example, deficiency of RAD51 foci has been used as a biomarker for the detection of DNA repair ability via immunohistochemistry.

However, as the test method is complex and the results may be affected by many factors, this test has not been widely used in clinics. Moreover, in the era of personalized cancer therapy, a greater number of potential functional markers and those that reflect early changes should be identified for the DNA damage, response and repair process, along with the development of more precise experimental methods.

In addition, an ethical issue remains to be addressed. In the real world, to test patient responses to cancer therapy, patients should be tested for potential DNA damage, response and repair defects using these early changing biomarkers, but these biomarkers must be activated using activators such as radiation, chemotherapy or immunotherapy, which would be very difficult for ethical reasons.

Therefore, prior to the clinical application of biomarkers, ethical issues should be addressed. Challenge III: The mechanism underlying the activity of DNA damage repair inhibitors in cancer therapy remains unclear, although a number of potential inhibitors have been approved for clinical trials.

Because their mechanisms have not been fully revealed, targeted therapies for cancer may have off-target effects. If we can solve this problem, targeted cancer therapy based on exploitation of DNA damage repair can be expected to improve therapeutic outcomes in the future. Recently, the combined usage of two or more inhibitors or therapy methods has increased in popularity.

Combined treatment may increase the efficacy of a therapy, but can also enhance toxicity or adverse effects, as its molecular mechanisms are much more complex and difficult to elucidate than those of single treatments.

Therefore, the creation of usage criteria and principles for combination treatment to ensure that such therapies are more effective against cancer and less harmful to health is urgently needed.

Challenge IV: Cancer resistance and normal tissue severe side-effects are the major obstacles to cancer therapy, the goal of personalized therapy strategy is to overcome these obstacles. Many resistance mechanisms have been reported to chemo-, radio-, and immuno-therapy.

Obviously, in the clinical setting, testing for gene mutation seven the secondary mutations in the recurrence tumors should be popularized and, most importantly, resistance mechanisms should be explored through cell, animal and clinical experiments in the near future.

Challenge V: Distilling the convergent findings obtained from the enormous amount of complicated research conducted on the relationships of DNA damage, response, and repair processes with cancer therapy remains a challenge, as does translating these basic research outcomes into clinical applications.

At present, a plethora of inhibitorsare in clinical trials or approved for clinical use that originated from basic cell and animal experiments. Additional biomarkers and agents show promise at the preclinical level, but their translation to the clinical setting has failed for many reasons, such as not providing superior therapeutic outcomes and serious adverse effects.

To achieve the purpose of translation study in the clinic in the future, more basic molecular mechanism of DNA damage and repair in cancer therapy should be extensive studied.

In conclusion, we believe that comprehensive research into the basic biology of DNA damage, response, and repair, accompanied by rapid development of new technologies and further progress in targeted cancer therapy, will drive significant advances in the near future.

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DNA Damage & Repair: Mechanisms for Maintaining DNA Integrity Greene, et al. Combining a PARP inhibitor with hyperthermia showed good treatment efficacy for cancers with HR deficiency. Mutagen 58 , — One of the important roles of DNA-PKcs is inducing ATM ataxia-telangiectasia mutated and ATR Rad3-related protein in response to DNA lesions. Thus, it has been suggested that improved cancer treatment outcomes may be obtained through targeting the DDR and DNA replication along with promotion of mitotic catastrophe in cancer cells. Each class has its specific substrates and potential roles. How such recognition occurs in mammals is not yet known.
DNA repair - Wikipedia

Some of them:. Nucleotide-excision repair proceeds most rapidly in cells whose genes are being actively transcribed on the DNA strand that is serving as the template for transcription. This enhancement of NER involves XPB, XPD, and several other gene products. The genes for two of them are designated CSA and CSB mutations in them cause an inherited disorder called Cockayne's syndrome.

The CSB product associates in the nucleus with RNA polymerase II , the enzyme responsible for synthesizing messenger RNA mRNA , providing a molecular link between transcription and repair. One plausible scenario: If RNA polymerase II, tracking along the template antisense strand , encounters a damaged base, it can recruit other proteins, e.

It can enlist the aid of enzymes involved in both base-excision repair BER and nucleotide-excision repair NER as well as using enzymes specialized for this function.

Mutations in either of these genes predisposes the person to an inherited form of colon cancer. So these genes qualify as tumor suppressor genes. coli , certain adenines become methylated shortly after the new strand of DNA has been synthesized. The MMR system works more rapidly, and if it detects a mismatch, it assumes that the nucleotide on the already-methylated parental strand is the correct one and removes the nucleotide on the freshly-synthesized daughter strand.

How such recognition occurs in mammals is not yet known. Synthesis of the repair patch is done by DNA polymerase delta. Cells also use the MMR system to enhance the fidelity of recombination; i. Ionizing radiation and certain chemicals can produce both single-strand breaks SSB s and double-strand breaks DSB s in the DNA backbone.

Breaks in a single strand of the DNA molecule are repaired using the same enzyme systems that are used in Base-Excision Repair BER. There are two mechanisms by which the cell attempts to repair a complete break in a DNA molecule:. Some of the same enzymes used to repair DSBs by direct joining are also used to break and reassemble the gene segments used to make.

Recombination between homologous chromosomes in meiosis I also involves the formation of DSBs and their repair. So it is not surprising that this process uses the same enzymes. Meiosis I with the alignment of homologous sequences provides a mechanism for repairing damaged DNA; that is, mutations.

in fact, many biologists feel that the main function of sex is to provide this mechanism for maintaining the integrity of the genome.

However, most of the genes on the human Y chromosome have no counterpart on the X chromosome, and thus cannot benefit from this repair mechanism.

They seem to solve this problem by having multiple copies of the same gene — oriented in opposite directions. Looping the intervening DNA brings the duplicates together and allowing repair by homologous recombination.

If the sequence used as a template for repairing a gene by homologous recombination differs slightly from the gene needing repair; that is, is an allele, the repaired gene will acquire the donor sequence. This nonreciprocal transfer of genetic information is called gene conversion.

Gene conversion during meiosis alters the normal mendelian ratios. Normally, meiosis in a heterozygous A , a parent will produce gametes or spores in a ratio; e. However, if gene conversion has occurred, other ratios will appear. The table lists by trade name as well as generic name some of the anticancer drugs that specifically target DNA.

The cancer patient has many other cell types that are also proliferating rapidly, e. Anticancer drugs also damage these — producing many of the unpleasant side effects of "chemo". Agents that damage DNA are themselves carcinogenic, and chemotherapy poses a significant risk of creating a new cancer, often a leukemia.

Search site Search Search. Go back to previous article. Sign in. Agents that Damage DNA Certain wavelengths of radiation including ionizing radiation such as gamma rays and X-rays and ultraviolet rays , especially the UV-C rays ~ nm that are absorbed strongly by DNA but also the longer-wavelength UV-B that penetrates the ozone shield.

Highly-reactive oxygen radicals produced during normal cellular respiration as well as by other biochemical pathways. Chemicals in the environment many hydrocarbons, including some found in cigarette smoke some plant and microbial products, e.

the aflatoxins produced in moldy peanuts Chemicals used in chemotherapy , especially chemotherapy of cancers. Types of DNA Damage All four of the bases in DNA A, T, C, G can be covalently modified at various positions.

One of the most frequent is the loss of an amino group "deamination" - resulting, for example, in a C being converted to a U. Mismatches of the normal bases because of a failure of proofreading during DNA replication.

Common example: incorporation of the pyrimidine U normally found only in RNA instead of T. Breaks in the backbone. Can be limited to one of the two strands a single-stranded break, SSB or on both strands a d ouble- s tranded b reak DSB.

Ionizing radiation is a frequent cause, but some chemicals produce breaks as well. Crosslinks Covalent linkages can be formed between bases on the same DNA strand "intrastrand" or on the opposite strand "interstrand". Several chemotherapeutic drugs used against cancers crosslink DNA.

Repairing Damaged Bases Damaged or inappropriate bases can be repaired by several mechanisms: Direct chemical reversal of the damage Excision Repair , in which the damaged base or bases are removed and then replaced with the correct ones in a localized burst of DNA synthesis.

There are three modes of excision repair, each of which employs specialized sets of enzymes. Base Excision Repair BER Nucleotide Excision Repair NER Mismatch Repair MMR The Nobel Prize in chemistry was shared by three researchers for their pioneering work in DNA repair: Tomas Lindahl BER , Aziz Sancar NER , and Paul Modrich MMR.

Direct Reversal of Base Damage Perhaps the most frequent cause of point mutations in humans is the spontaneous addition of a methyl group CH 3 - an example of alkylation to Cs followed by deamination to a T. Base Excision Repair BER The steps and some key players: removal of the damaged base estimated to occur some 20, times a day in each cell in our body!

by a DNA glycosylase. We have at least 8 genes encoding different DNA glycosylases each enzyme responsible for identifying and removing a specific kind of base damage.

removal of its deoxyribose phosphate in the backbone, producing a gap. We have two genes encoding enzymes with this function. replacement with the correct nucleotide. This relies on DNA polymerase beta , one of at least 11 DNA polymerases encoded by our genes.

ligation of the break in the strand. Two enzymes are known that can do this; both require ATP to provide the needed energy.

Methylation of guanine. The methyl group can be removed from the damaged, methylated base by an enzyme found in the cell. Base excision repair. Base excision repair is a mechanism used to detect and remove certain types of damaged bases. A group of enzymes called glycosylases play a key role in base excision repair.

Each glycosylase detects and removes a specific kind of damaged base. For example, a chemical reaction called deamination can convert a cytosine base into uracil, a base typically found only in RNA.

To prevent such mutations, a glycosylase from the base excision repair pathway detects and removes deaminated cytosines. Base excision repair of a deaminated cytosine. Deamination converts a cytosine base into a uracil. This results in a double helix in which a G in one strand is paired with a U in the other.

The U was formerly a C, but was converted to U via deamination. The base-less nucleotide is removed, leaving a 1-nucleotide hole in the DNA backbone.

The hole is filled with the right base by a DNA polymerase, and the gap is sealed by a ligase. Nucleotide excision repair. Nucleotide excision repair is another pathway used to remove and replace damaged bases. Nucleotide excision repair detects and corrects types of damage that distort the DNA double helix.

Nucleotide excision repair is also used to fix some types of damage caused by UV radiation, for instance, when you get a sunburn. UV radiation can make cytosine and thymine bases react with neighboring bases that are also Cs or Ts, forming bonds that distort the double helix and cause errors in DNA replication.

Nucleotide excision repair of a thymine dimer. UV radiation produces a thymine dimer. In a thymine dimer, two Ts that are next to each other in the same strand link up via a chemical reaction between the bases.

This creates a distortion in the shape of the double helix. Once the dimer has been detected, the surrounding DNA is opened to form a bubble. Enzymes cut the damaged region thymine dimer plus neighboring regions of same strand out of the bubble.

A DNA polymerase replaces the excised cut-out DNA, and a ligase seals the backbone. In nucleotide excision repair, the damaged nucleotide s are removed along with a surrounding patch of DNA.

In this process, a helicase DNA-opening enzyme cranks open the DNA to form a bubble, and DNA-cutting enzymes chop out the damaged part of the bubble. Double-stranded break repair. Some types of environmental factors, such as high-energy radiation, can cause double-stranded breaks in DNA splitting a chromosome in two.

This is the kind of DNA damage linked with superhero origin stories in comic books, and with disasters like Chernobyl in real life. Double-stranded breaks are dangerous because large segments of chromosomes, and the hundreds of genes they contain, may be lost if the break is not repaired.

Two pathways involved in the repair of double-stranded DNA breaks are the non-homologous end joining and homologous recombination pathways. In non-homologous end joining , the two broken ends of the chromosome are simply glued back together.

A double-stranded break may be repaired by non-homologous end joining. The chromosome is "glued" back together, usually with a small mutation at the break site. Diagram based on similar diagram in Alberts et al.

In homologous recombination , information from the homologous chromosome that matches the damaged one or from a sister chromatid, if the DNA has been copied is used to repair the break. In this process, the two homologous chromosomes come together, and the undamaged region of the homologue or chromatid is used as a template to replace the damaged region of the broken chromosome.

The double-stranded break may be repaired by homologous recombination. The broken chromosome pairs up with its homologue.

The damaged region is replaced via recombination, using sequences copied from the homologue. DNA proofreading and repair in human disease. Evidence for the importance of proofreading and repair mechanisms comes from human genetic disorders.

In many cases, mutations in genes that encode proofreading and repair proteins are associated with heredity cancers cancers that run in families. For example:. Since mismatched bases are not repaired in the cells of people with this syndrome, mutations accumulate much more rapidly than in the cells of an unaffected person.

This can lead to the development of tumors in the colon. People with xeroderma pigmentosum are extremely sensitive to UV light. This condition is caused by mutations affecting the nucleotide excision repair pathway.

When this pathway doesn't work, thymine dimers and other forms of UV damage can't be repaired. Want to join the conversation? Log in. Sort by: Top Voted.

Posted 8 years ago. why would cells ever apply non-homologous end joining if there is a cleaner and safer alternative? Do they only do that when there's no undamaged template available? Downvote Button navigates to signup page.

Flag Button navigates to signup page. Show preview Show formatting options Post answer. Posted 4 years ago. In the absense of homologous chromosome when DNA hasn't undegone replication yet non homologous end joining is done.

Comment Button navigates to signup page. Matthew Winkler. Posted 7 years ago. Is there potential, during any of the above proofreading methods to "correct" the template DNA rather than the newly-formed strand? Satwik Pasani.

By potential, do you mean that is mistakenly correcting the template strand possible? If so, then yes it is. The mechanism to determine which is the newly-formed and the template strand isn't perfect and relies on methylation and other epigenetic markers.

These can fail. Some repair machineries are anyway strand non-specific, and some are even sequence non-specific see Non Homologous End Joining, which is the last resort at DNA stability. rokaia Posted 6 years ago. what happen if DNA have uracil instead of uracil?

how can DNA repair it? and what are the reasons that DNA contain thymine not uracil. In your question — "what happen if DNA have uracil instead of uracil? I'm not sure what you really want to know — as it says in the article, uracil in DNA is usually recognized as a mistake and removed by the Base Excision Repair pathway There are a number of proposed reasons why thymine is used in DNA.

There are enzymes that specifically recognize and remove uracil but not thymine from DNA and this helps suppress what would otherwise be a major contributor to the rate mutations. Posted 9 months ago. Why is thymine in DNA and uracil in RNA?

5.13: DNA Repair Low-carb and balanced nutrition reaction of repalr and di-functional alkylating agents with rfpair acids. Genes DNA repair. The production DA mutations by X-Rays. DNA repair breaks DNA repair not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them. Frankenberg-Schwager, M. What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. Key points:.
Human DNA repair genes

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Considering Dual Enrollment? Learn More Now! Need a Chemistry Tutor? Details Here. Evolution by natural selection is also possible due to random mutations that occur within germ cells.

Occasionally, germline mutations may lead to a beneficial mutation that enhances the survival of an individual within a population. If this gene proves to enhance the survival of the population, it will be selected for over time within the population and cause the evolution of that species.

An example of a beneficial mutation is the case a population of people that show resistance to HIV infection. Since the first case of infection with human immunodeficiency virus HIV was reported in , nearly 40 million people have died from HIV infection, the virus that causes acquired immune deficiency syndrome AIDS.

There is no cure for HIV infection, but many drugs have been developed to slow or block the progression of the virus. Unfortunately, this is also a part of the world where prevention strategies and drugs to treat the infection are the most lacking.

Figure 2. Figure from: P arker, et al Microbiology from Openstax. In recent years, scientific interest has been piqued by the discovery of a few individuals from northern Europe who are resistant to HIV infection. In , American geneticist Stephen J. CCR5 is a coreceptor found on the surface of T-cells that is necessary for many strains of the virus to enter the host cell.

The mutation leads to the production of a receptor to which HIV cannot effectively bind and thus blocks viral entry.

People homozygous for this mutation have greatly reduced susceptibility to HIV infection, and those who are heterozygous have some protection from infection as well. It is not clear why people of northern European descent, specifically, carry this mutation, but its prevalence seems to be highest in northern Europe and steadily decreases in populations as one moves south.

Research indicates that the mutation has been present since before HIV appeared and may have been selected for in European populations as a result of exposure to the plague or smallpox. This mutation may protect individuals from plague caused by the bacterium Yersinia pestis and smallpox caused by the variola virus because this receptor may also be involved in these diseases.

The age of this mutation is a matter of debate, but estimates suggest it appeared between years to years ago, and may have been spread from Northern Europe through Viking invasions. This exciting finding has led to new avenues in HIV research, including looking for drugs to block CCR5 binding to HIV in individuals who lack the mutation.

Although DNA testing to determine which individuals carry the CCR5-delta 32 mutation is possible, there are documented cases of individuals homozygous for the mutation contracting HIV. For this reason, DNA testing for the mutation is not widely recommended by public health officials so as not to encourage risky behavior in those who carry the mutation.

Nevertheless, inhibiting the binding of HIV to CCR5 continues to be a valid strategy for the development of drug therapies for those infected with HIV.

Bases can become oxidized, alkylated, or hydrolyzed through interactions with these agents. For example, methyl CH 3 chemical groups are frequently added to guanine to form 7-methylguanine; alternatively, purine groups may be lost.

All such changes result in abnormal bases that must be removed and replaced. Thus, enzymes known as DNA glycosylases remove damaged bases by literally cutting them out of the DNA strand through cleavage of the covalent bonds between the bases and the sugar-phosphate backbone.

The resulting gap is then filled by a specialized repair polymerase and sealed by ligase. Many such enzymes are found in cells, and each is specific to certain types of base alterations. Yet another form of DNA damage is double-strand breaks, which are caused by ionizing radiation, including gamma rays and X-rays.

These breaks are highly deleterious. In addition to interfering with transcription or replication, they can lead to chromosomal rearrangements , in which pieces of one chromosome become attached to another chromosome.

Genes are disrupted in this process, leading to hybrid proteins or inappropriate activation of genes. A number of cancers are associated with such rearrangements.

Double-strand breaks are repaired through one of two mechanisms: nonhomologous end joining NHEJ or homologous recombination repair HRR. In NHEJ, an enzyme called DNA ligase IV uses overhanging pieces of DNA adjacent to the break to join and fill in the ends.

Additional errors can be introduced during this process, which is the case if a cell has not completely replicated its DNA in preparation for division. In contrast, during HRR, the homologous chromosome itself is used as a template for repair. Mutations in an organism's DNA are a part of life.

Our genetic code is exposed to a variety of insults that threaten its integrity. But, a rigorous system of checks and balances is in place through the DNA repair machinery.

The errors that slip through the cracks may sometimes be associated with disease, but they are also a source of variation that is acted upon by longer-term processes, such as evolution and natural selection. Branze, D.

Regulation of DNA repair throughout the cell cycle. Nature Reviews Molecular Cell Biology 9 , — doi pdf link to article. Crowe, F. A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis Springfield, Illinois, Charles C.

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DNA Replication and Causes of Mutation. Genetic Mutation. Major Molecular Events of DNA Replication. Semi-Conservative DNA Replication: Meselson and Stahl. Barbara McClintock and the Discovery of Jumping Genes Transposons. Functions and Utility of Alu Jumping Genes. Transposons, or Jumping Genes: Not Junk DNA?

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Colinearity and Transcription Units. Discovery of DNA as the Hereditary Material using Streptococcus pneumoniae. Discovery of DNA Structure and Function: Watson and Crick. Isolating Hereditary Material: Frederick Griffith, Oswald Avery, Alfred Hershey, and Martha Chase.

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