|Year : 2018 | Volume
| Issue : 5 | Page : 539-545
Cancer prevention, the need to preserve the integrity of the genome at all cost
MT Okafor1, TU Nwagha2, C Anusiem1, UA Okoli3, NI Nubila1, F Al-Alloosh4, IJ Udenyia1
1 Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria Enugu Campus, Nigeria
2 Department of Haematology and Immunology, College of Medicine, University of Nigeria, Nsukka, Nigeria
3 Department of Biochemistry College of Medicine, University of Nigeria, Nsukka, Nigeria
4 Department of Surgical Oncology, Al-Amal National Hospital for Cancer Management, Iraq, Baghdad
|Date of Acceptance||16-Feb-2018|
|Date of Web Publication||4-May-2018|
Dr. T U Nwagha
Department of Haematology and Immunology, College of Medicine, University of Nigeria Nsukka, University of Nigeria Teaching Hospital, Enugu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: The entire genetic information carried by an organism makes up its genome. Genes have a diverse number of functions. They code different proteins for normal proliferation of cells. However, changes in the base sequence of genes affect their protein by-products which act as messengers for normal cellular functions such as proliferation and repairs. Salient processes for maintaining the integrity of the genome are hinged on intricate mechanisms put in place for the evolution to tackle genomic stresses. Aim: To discuss how cells sense and repair damage to their deoxyribonucleic acid (DNA) as well as to highlight how defects in the genes involved in DNA repair contribute to cancer development. Methodology: Online searches on the following databases such as Google Scholar, PubMed, Biomed Central, and SciELO were done. Attempt was made to review articles with keywords such as cancer, cell cycle, tumor suppressor genes, and DNA repair. Results: The cell cycle, tumor suppression genes, DNA repair mechanism, as well as their contribution to cancer development, were discussed and reviewed. Conclusion: Knowledge on how cells detect and repair DNA damage through an array of mechanisms should allay our anxiety as regards cancer development. More studies on DNA damage detection and repair processes are important toward a holistic approach to cancer treatment.
Keywords: Cancer, deoxyribonucleic acid, genes, genome
|How to cite this article:|
Okafor M T, Nwagha T U, Anusiem C, Okoli U A, Nubila N I, Al-Alloosh F, Udenyia I J. Cancer prevention, the need to preserve the integrity of the genome at all cost. Niger J Clin Pract 2018;21:539-45
|How to cite this URL:|
Okafor M T, Nwagha T U, Anusiem C, Okoli U A, Nubila N I, Al-Alloosh F, Udenyia I J. Cancer prevention, the need to preserve the integrity of the genome at all cost. Niger J Clin Pract [serial online] 2018 [cited 2018 May 26];21:539-45. Available from: http://www.njcponline.com/text.asp?2018/21/5/539/231891
| Introduction|| |
Current studies on the human genome show that it consists of about 22,000 genes. They are transferred from one organism to another and code different proteins and enzymes that carry out biochemical reactions of life. However, cell growth and proliferation may become abnormal when genes responsible for their normal proliferation are lost.,,
In 1944, Deoxyribonucleic acid (DNA) was proven to be the chemical entity, in which genetic information of cells is carried in. Years on, Watson and Crick showed with clarity the structure of the DNA. To avoid mutations, DNA replication is done with high fidelity. Replication errors may arise during DNA synthesis from mutagenic agents such as chemicals, viruses, ionizing, and ultraviolet radiations which constantly attack the DNA. Are we all going to succumb to malignant diseases that may develop from these events knowing that mutations tip the balance of the perturbed genome in favor of malignancy?
Vast literature on how cells maintain the integrity of its genome exists. It can be justifiably argued that available literature on different mechanisms in humans to avert malignancies has outpaced the speed of proliferation of even the most aggressive tumors. Thus, an overview of these mechanisms with emphasis on how cells sense, repair DNA damage, and how defects in genes involved in DNA repair contribute to cancer development will pave way for easier understanding of how the integrity of the genome is maintained.
| Methodology|| |
Online searches on the following databases such as Google Scholar, PubMed, Biomed Central, and SciELO, were done. Attempt was made to review articles with keywords such as cancer, cell cycle, tumor suppressor genes (TSGs), and DNA repair. Articles that published from 2000 till date were reviewed.
| Results|| |
The Cell Cycle
Phases of the cell cycle have been well known for about 40 years. Key molecular steps on how cells grow and divide have been shown. The cell cycle is made up of phases comprised of DNA replication and cell division. These processes are carefully regulated in normal cells. Phases of the cell cycle is divided into G1, S (where DNA replication occur), second gap phase G2, and mitosis phase. During mitosis, two daughter cells which can begin a new cell cycle are produced. G0 phase accounts for cells in quiescent forms.,
In late G1 phase, cells acquire the ability to go through the cell cycle with relative independence from extracellular signals. This point in the late G1 is called restriction point. Loss of restriction point possibly is a universal step toward cancer development. Simply put, dysfunction of G1 cell cycle progression promotes tumor formation.,,
Cell cycle checkpoints
Each phase of the cell cycle has monitoring mechanisms known as checkpoints This is to say that cell cycle checkpoints are genetically determined signaling pathways that delay execution of certain cell cycle events until earlier events are deemed satisfactory.,, The CDC2 gene discovery in the 1960s turned out to be a gold mine of information on cell cycle regulation. It codes a kinase, an enzyme that participates in many aspects of the cell function. The engine of the cell cycle is fueled by different proteins and enzymes: cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs), which are responsible for the progression of the cell cycle from one phase to another and also inhibiting the cell cycle., See [Figure 1]. When coupled with an associate cyclin, CDKs phosphorylate and activate protein products of different TSGs, CDKI genes, and DNA repair genes.
|Figure 1: Tumor suppressor gene active at different cell cycle checkpoints|
Click here to view
During interphase, DNA damage initiates cell cycle arrest and allows time for repair. The primary goal of different checkpoints to genomic stress is to inactivate CDKs or maintain them in an inactivate state until the cell is deemed fit to progress further into the cell cycle. Evidence has also shown that perturbation of these is another step closer to cancer development.
Apart from cell cycle progression and inhibition, a labyrinth of cyclins, CDKs, and CDKIs also participates in DNA repair. For clarity and brevity, we concentrate on some TSGs active at each checkpoint of the cell cycle. It is important to note that there may be some overlap of these TSGs at different checkpoints of the cell cycle.
These genes work in a concerted fashion by assisting one another and acting as a backup in halting the progression of the cell cycle at different check points at the event of DNA damage. They may also initiate DNA repair by signaling recruitment of protein complexes for repairs at the site of DNA damage. TSGs may also be viewed as housekeepers or gatekeepers in relation to their functions. The housekeepers orchestrate DNA repair by recruiting DNA repair proteins at the site of DNA damage along with other functions. The gatekeepers initiate apoptosis or senescence to eliminate cells whose DNA damage is beyond repair. However, some TSGs such as p53 have both housekeeper and gatekeeper functions.
G1 phase and related tumor suppressor genes
A lot is known about the retinoblastoma gene (Rb) as it was the first TSG to be discovered. When activated in response to DNA damage, pRb the protein product of Rb gene put brakes on how the cell advances into the cell cycle by binding to the transcription factor E2F in the hypophosphorylated form. pRb is accountable for majority of G1 checkpoint activities., A study from assay protocols in wild-type Rb in Rb-mutant cells demonstrates that Rb can stop the cell cycle and even induce senescence in cells with badly damaged DNA.
The ataxia telangiectasia mutated (ATM) gene has its central role in the repair of double-strand DNA breaks. Its response to DNA damage includes numerous processes with recognition of damaged DNA, recruitment of repair proteins, as well as signaling to different cell cycle checkpoints.,
When activated, ChK2 gene encoded protein is known to inhibit Cdc25C phosphatase preventing entry into mitosis and cell cycle arrest in G1. A mutation in this gene is a predisposition to familial breast cancers as well as other types of malignancies., When activated, ChK2 gene encoded protein is known to inhibit CDC25C phosphatase preventing entry into mitosis and cell cycle arrest in G1. A mutation in this gene is a predisposition to familial breast cancers as well as other types of malignancies.,
Numerous academic write ups refer to p53 as the master guardian of the genome, molecular policeperson, or executioner. It brings about its tumor suppressor activity in part by upregulating CDKI p21, thereby stopping the cell cycle in the event of DNA damage and giving the cell an opportunity to repair the damage. If the damage is beyond repair, the cells undergo a form of programmed cell death known as apoptosis which is vital in the elimination of damaged cells. Both p53 and p21 appear to be essential for maintaining G1 and G2 checkpoints.,, Different cytotoxic agents used in treating cancers can induce the expression of p53 and ultimately give rise to apoptosis in these cells. Furthermore, p53 involvement in regulating the expression of proteins, especially the Bcl-2 family, which are also involved in the process of apoptosis, is worthy of note.
S/G2 phase and related tumor suppressor genes
Similar TSGs play different roles at S and G2 checkpoints. It is still critical that cells in need of repair at G2 and S checkpoints get repaired because the probability that the cells with damaged DNA get to the end of the cell cycle increases as cells advance into the cell cycle.
The discovery of BRCA1 and BRCA2 genes raised questions as of whether they should be classified as TSGs. They are actually involved in DNA repair and maintenance of genomic integrity and are therefore considered as “caretakers” rather than “gatekeepers” in respect to other TSGs. They are wildly expressed in different tissues during the S and G2 phases. Nullizygous BRCA1 or BRCA2 embryos die around the time of gastrulation. Surprisingly, these embryos reveal a proliferative defect and induction of the p53-dependent cell cycle inhibitor p21.
Identification of nibrin or Nijmegen breakage syndrome 1 (NBS1) gene highlighted the molecular mechanisms of double-strand break (DSB) repair in response to DNA damage and senescence if the need arises., The first evidence of possible association NBS1 carriers and cancer risk came from family data studies, highlighting that blood relatives of NBS patients with the 657del5 founder mutation had a high probability to develop malignancy. On DNA damage, NBS1 protein products recruit and forms multimeric repair complexes and channel them toward the site of DNA damage. These processes correspond to S and G2 cell cycle checkpoints.
M phase checkpoint and related tumor suppressor genes
Mitosis checkpoint is the last checkpoint of the cell cycle. A biological system with carefully designed backups to avert malignancies as the cell cycle is most likely to fail on exhaustion of these backups, irrespective of how tightly regulated they are.
Prior the mitosis phase in the cycle, the M checkpoint also validates the integrity of the cell before it goes through mitosis or meiosis to avoid propagating genetic defects to daughter cells. The centrosome as the primary microtubule-organizing center plays an essential role in maintaining chromosome stability. Aurora kinases: BubR1, Mad1, and Mad2 among other kinases control the M checkpoint. BubR1 protein kinase (PK) is central to the mitotic checkpoint. Microtubules of cells in need of repair recruit BubR1 and Mad1 and get attached to kinetochores giving rise to an inhibitory effect mitotic arrest as a consequence.
| Deoxyribonucleic Acid Repair|| |
Detection of DNA damage is a crucial step in maintaining the integrity of the genome. Repair of the damage is another important factor. Eukaryotic cells use multiple pathways to maintain genomic integrity in response to DNA damage. The different mechanisms employed in DNA repair are direct repair, base excision repair (BER), nucleotide excision repair (NER), and repair of DSBs (which can be homologous or nonhomologous). These repair mechanisms act in a similar manner in the sense that the damaged DNA is excised, re-synthesized, and ligated., see [Figure 2].
|Figure 2: Different types of deoxyribonucleic acid damage and associated repair mechanisms|
Click here to view
Direct repair acts directly on damaged nucleotides and converting them to their original structure. Only few forms of damaged nucleotides can be repaired this way. It repairs nicks and some forms of alkylation. Nicks are repaired by direct repair only if the damage involves a broken phosphodiester bond without damage to the 5-phosphate and three hydroxyl groups of the nucleotides. Removal of miscoding alkylating lesion, e.g., O-methyl guanine is removed by O-methylguanine-DNA methyl transferase in humans.
Nucleoside excision repair
The foremost contribution of excision repair processes to recovery of cells from DNA damage was manifested from the greatly increased sensitivity of mutant cells that were defective in this repair process. NER is the major DNA repair mechanism and plays a backup to other DNA repair mechanisms. It is also a pathway for the recognition and repair of a wide range of DNA lesions., Transcription factor IIH (basal transcription factor) is a ten-subunit protein complex required for unwinding of DNA for repair. Photosensitive form of trichotiodystrophy is caused by inherited mutations of three of the subunits of basal transcription factor, an important complex in NER. NER is essential in repairing thymine–thymine dimmers caused by ultraviolet light. Thymine–thymine dimers disrupt both replication and transcription of DNA. Genes such as XPA-XPG, CSA, and CSB are worthy of note in NER because they play important roles in this repair system. Furthermore, components of NER pathway were in part discovered by mutation in these genes.,
Base excision repair
BER is the main system employed in removing nucleotides damaged by intracellular processes such as free radical oxidations and deamination of cytosine. Lesions from oxidation and deamination cause little distortion to the DNA and are tackled by BER. The altered base is hydrolyzed by a family of N-glycosidases leaving an abasic site (AP site) that is cleaved by an AP endonuclease. New DNA is synthesized at the site by a ligase, thus completing the repair.,,
Repair of double-strand breaks
DNA DSBs are usually secondary to harmful agents such as ionizing radiation and chemical agents. DSBs must be repaired as they bring about the disruption of genomic integrity. Two different pathways involved in DSB to the DNA are homologous recombination or nonhomologous end joining (HR and NHEJ).,, Response to DSBs is a complex signaling network which activates several metabolic processes with the key activator protein ATM. This targets and activates the DNA repair enzyme polynucleotide kinase/phosphate which is crucial for cellular survival after a DSB. ATM also phosphorylates a range of substrates that include p53, H2AX, BRCA1, BLM, FANCD2, and NBS1 and many others involved in repair of double-strand DNA breaks. NBS1 forms a complex with MRE11-RAD50 nuclease (mre11-rad50-nbs1 [MRN] complex) and recruits these proteins to the site of DSBs in both HR and NHREJ. Furthermore, MRN complex defects in cells make them very sensitive to DNA-damaging agents.,, Underlying mechanism in aforementioned types of DSBs in the DNA is similar in respect to their associated DNA repair genes and protein complexes. A major difference is use of available broken end of a DNA segment to serve as a repair template for homologous repair and not for nonhomologous repair.
Nonhomologous end joining
It is a major pathway for repair of DNA DSBs of somatic cells. Three mechanisms have been defined by studies for NHEJ: single strand, template directed, and postrepair ligations. Key biochemical enzymes and proteins involved in NHEJ include DNA ligase IV, Pol X family DNA polymerases, and Ku proteins.,, A key role in NHEJ is played by DNA-dependent PK (DNA-PK) which has a DSB recognition role and activation of other components involved in the repair. DNA-PK is made up of a Ku protein and a catalytic sub-unit. Ku protein has a strong affinity for DNA broken ends. It holds them together while the catalytic subunit of DNA-PK is activated as DNA ends are processed, aligned, and ligated by the enzyme DNA ligase IV and its binding partner XRCC4. Joining of broken DNA ends in NHEJ has little or no base pairing. This makes this repair pathway error prone.,,
A ubiquitous process and less error prone pathway for DNA DSB repair with a highly accurate template for the process in the S or G2 phase of the cell cycle.,, Undamaged sister chromatid is used as a template for synthesizing DNA at the damaged point. When DSB occurs, ATM kinase is activated leading to MRN complex activation at the site of the damage. Rad51 and Rad54 proteins are key components of the HR machinery. MRN complex prepares a 3 tail for Rad51 nucleoprotein filament which invades the homologous duplex. Rad54 does a homologous sequence search, and the invading strand (a copy) is displaced by the 3 end of the invading sequences. Strand invasion may be one ended or two ended and converted to Rad51 nucleofilaments with both invading the homologous sequence. DNA synthesis follows one-ended filament invasion.,, Newly synthesized DNA dissociates from the repair template and gets attached to the broken duplex. Resulting microfilament may give rise to holiday junctions and branch migrations and must be resolved by a group of highly specialized endonucleases which catalyze cleavage of these junctions. These gaps are resolved by Rad51 and its paralogs XRCC2, XRCC3, and Rad51B., BRCA1 and two genes respond to DSBs. However, BRCA1 have been shown orchestrate homology directed repairs. Controlled HR is crucial for the preservation of repetitive sequences of ribosomal gene cluster because uncontrolled HR may lead to chromosome translocations, loss of heterozygosity, and deletion of repetitive sequences.
Mismatch repair (MMR) mechanism repairs copy errors made during DNA replication. Two mismatch recognition complexes found in humans are hMuts and hMuts. They both either bind to a loop or a mismatch. After recognition, other complexes post meiotic segregation increased 2 (PMS2) with their components assemble a repair complex and the DNA mismatch is removed, re-synthesized, and ligated to complete the repair.
| Defects in Deoxyribonucleic Acid Repair Genes and How they Contribute to Cancer Development|| |
Defects in DNA repair genes are forerunners to different cancers. Mutation in MMR genes MSH1, MSH2, and MSH6 may give rise to Lynch syndrome. Lifetime risk of developing colon cancers in people with mutation in these MMR genes is about 75% by 70 years. Microsatellite instability (short-repeated segments of DNA all through the genome) is corrected by MMR process.,
About 5%–10% of breast and ovarian cancers are believed to be hereditary with many of these secondary to germline mutations in BRCA1 and BRCA2 genes. They are vital for DSB repair by HR. Tumors deficient in these genes are very susceptible to DSB by chemotherapy.,
NBS is rare autosomal recessive disorder increase predisposition to different cancers. Affected people have a mutation in their NBS1 gene. Therefore, they cannot evoke the MRN complex activated by protein products of the NBS1 gene when there is DNA damage. Over 90% of patients homozygous for a founder mutation in 65del5 in NBS gene appear to be more at risk with cancer development. People who suffer from xeroderma pigmentosum and Cockayne syndrome have increased susceptibility to ultra violet light induced cancers because of mutations in their XPA-XPG genes involved in NER See [Figure 3].,
|Figure 3: Defects in deoxyribonucleic acid repair gene and associated cancers to these defects|
Click here to view
| Conclusion|| |
Knowledge on how cells detect and repair DNA damage through an array of mechanisms should allay our anxiety as regards cancer development. However, some people may lack this ability due to some defects in their DNA repair, cell cycle regulation, and TSGs. Studies on DNA damage detection and repair processes as well as creation of inhibitors and activators these systems should be encouraged because, when cells become malignant, their compassion may be far from our reach.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weinberg RA. The Biology of Cancer. 2 ed. NewYork: Garland Science; 2013. p. 53-8.
Collins FS, Jegalin KG. Deciphering the Code of Life Scientific American. 1999;281:86-91. Doi:10.1038/scientificamerican1299-86.
Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al
. Human gene mutation database (HGMD): 2003 update. Hum Mutat 2003;21:577-81.
Rossnerova A, Pokorna M, Svecova V, Rossner P. Adaptation of the environment: Current knowledge, clues from Czech cytogenic and omic biomonitoring studies and possible mechanisms. Mutations Res Rev Mutation Res 2017;773:188-203.
MacDonald F, Ford CHJ, Casson A. Molecular Biology of Cancer. 2 ed. NewYork: Taylor and Francis Group; 2004. p. 138-45.
Hunt T, Nasmyth K, and Novak B. The cell cycle. Philosophical Transactions of the Royal Society. Vol. 27. London. Series B, Biological Sciences Royal Society; 2011. p. 3494-7.
Foster DA, Yellen P, Xu L, Saqcena M. Regulation of G1 cell cycle progression: Distinguishing the restriction point from a nutrient-sensing cell growth checkpoint(s). Genes Cancer 2010;1:1124-31.
Aguda BD. Cell Cycle Control: The Restriction Point. eLS. 2015;1-5. Doi: 10.1002/9780470015902.
Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle 2002;1:103-10.
Knowles M, Selby P. Introduction to the Cellular and Molecular Biology of Cancer. 4th
ed.: NewYork Oxford University Press; 2005. p. 209-15.
Nakanishi M, Shimada M, Niida H. Genetic instability in cancer cells by impaired cell cycle checkpoints. Cancer Sci 2006;97:984-9.
Shimada M, Nakanishi M. DNA damage checkpoints and cancer. J Mol Histol 2006;37:253-60.
Barnum KJ, O'Connell MJ. Cell cycle regulation by checkpoints. Methods Mol Biol 2014;1170:29-40.
Masaki T, Shiratori Y, Rengifo W, Igarashi K, Yamagata M, Kurokohchi K, et al
. Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis. Hepatology 2003;37:534-43.
Cotran R, Kumar V, Collin T. Robbins Pathological Basis of Disease. 6th
ed. Philadelphia: W.B. Saunders Company; 1999. p. 517-20.
Giacinti C, Giordano A. RB and cell cycle progression. Oncogene 2006;25:5220-7.
Zhu L. Tumour suppressor retinoblastoma protein Rb: A transcriptional regulator. Eur J Cancer 2005;41:2415-27.
Milne RL. Variants in the ATM gene and breast cancer susceptibility. Genome Med 2009;1:12.
Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene 2006;25:5906-11.
Nevanlinna H, Bartek J. The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 2006;25:5912-9.
Toledo F, Bardot B. The core domain of the p53 protein has been found to affect microRNA processing. Its third known activity. Most cancerous p53 mutations affect this domain and may abolish all tunor suppressor functions. Nature 2009;460:466-7.
Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, et al
. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 1998;282:1497-501.
Cotter TG. Apoptosis and cancer: The genesis of a research field. Nat Rev Cancer 2009;9:501-7.
Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002;108:171-82.
Scully R, Livingston DM. In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature 2000;408:429-32.
Matsuura S, Kobayashi J, Tauchi H, Komatsu K. Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys 2004;38:65-80.
di Masi A, Antoccia A. NBS1 heterozygosity and cancer risk. Curr Genomics 2008;9:275-81.
Tauchi H, Matsuura S, Kobayashi J, Sakamoto S, Komatsu K. Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene 2002;21:8967-80.
Wang Y, Ji P, Liu J, Broaddus RR, Xue F, Zhang W, et al
. Centrosome-associated regulators of the G(2)/M checkpoint as targets for cancer therapy. Mol Cancer 2009;8:8.
Bolanos-Garcia VM, Blundell TL. BUB1 and BUBR1: Multifaceted kinases of the cell cycle. Trends Biochem Sci 2011;36:141-50.
Anindya R, Mari PO, Kristensen U, Kool H, Giglia-Mari G, Mullenders LH, et al
. A ubiquitin-binding domain in cockayne syndrome B required for transcription-coupled nucleotide excision repair. Mol Cell 2010;38:637-48.
Lavrik OI. DNA repair: A key molecular mechanism stabilizing the genome. Biokhimiya 2011;37:80-94.
Harvey L, Baltimore D. Molecular Cell Biology. 6th
ed. NewYork :Freeman; 2006. p. 211-2.
King RJ, Robbins M. Cancer Biology. 3rd
ed. Harlow: Pearson Prentice Hall, 2006. p. 65-70.
Brown TA. Genomes. 3rd
ed. NewYork: Garland Science; 2007. p. 18.
Thompson LH. Nucleotide excision repair: Its relation to human disease. In: Nickoloff JA, Hoekstra MF, editors. DNA Damage and Repair. Repair in Higher Eukaryotes. Vol. 2. Totowa (New Jersey): Humana Press; 1998. p. 335-93.
Sancar A, Tang MS. Nucleotide excision repair. Photochem Photobiol 1993;57:905-21.
Reardon JT, Sancar A. Nucleotide excision repair. Prog Nucleic Acid Res Mol Biol 2005;79:183-235.
Theil AF, Nonnekens J, Wijgers N, Vermeulen W, Giglia-Mari G. Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts. Mol Cell Biol 2011;31:3630-8.
Vita IE. Hellman and Rosenberg: Cancer Principles and Practice of Oncology. 8 ed. Philadelphia: Lippincott Wilkins; 2009. p. 84-95.
Krokan HE, Bjørås M. Base excision repair. Cold Spring Harb Perspect Biol 2013;5:a012583.
Fromme JC, Verdine GL. Base excision repair. Adv Protein Chem 2004;69:1-41.
Seeberg E, Eide L, Bjørås M. The base excision repair pathway. Trends Biochem Sci 1995;20:391-7.
Jasin M, Rothstein R. Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol 2013;5:a012740.
Dudás A, Chovanec M. DNA double-strand break repair by homologous recombination. Mutat Res 2004;566:131-67.
Brandsma I, Gent DC. Pathway choice in DNA double strand break repair: Observations of a balancing act. Genome Integr 2012;3:9.
Segal-Raz H, Mass G, Baranes-Bachar K, Lerenthal Y, Wang SY, Chung YM, et al
. ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair. EMBO Rep 2011;12:713-9.
Garner KM, Eastman A. Variations in mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel. BMC Cancer 2011;11:206:1-13.
Lee JH, Paull TT. ATM activation by DNA double-strand breaks through the mre11-rad50-nbs1 complex. Science 2005;308:551-4.
Derbshire MK, Epstein LH, Young CS, Munz PL, Fishel R. Homologous recombination in humans. Mol Cell Biol 1994;14:156-69.
Roth DB, Wilson JH. Nonhomologous recombination in mammalian cells: Role for short sequence homologies in the joining reaction. Mol Cell Biol 1986;6:4295-304.
Wilson TE. Non-homologous end joining: Mechanisms, conservation and relationship to illegitimate recombination. In: Aguilera A, Rothstein R. Molecular Genetics of Recombination (Topics in Current Genetics). Germany, New York: Springer-Verlag, Berlin/Heidelberg; 2007. p. 487-513.
Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, et al
. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J 1998;17:5497-508.
Xing M, Yang M, Huo W, Feng F, Wei L, Jiang W, et al
. Interactome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway. Nat Commun 2015;6:6233.
Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 2010;79:181-211.
Hanakahi LA, West SC. Specific interaction of IP6 with human ku70/80, the DNA-binding subunit of DNA-PK. EMBO J 2002;21:2038-44.
Ochi T, Wu Q, Blundell TL. The spatial organization of non-homologous end joining: From bridging to joining. DNA Repair (Amst) 2014;17:98-109.
Moyanhan ME, Cui TY, Jasin M. Homology-directed DNA repair, mitomycin-C resistance and chromosome stability is restored with correction of BRCA1 mutation. Cancer Res 2001;61:4842-50.
Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 2008;18:99-113.
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ. The fanconi anemia gene promotes homologous recombination and error prone DNA repair. Sci Direct 2004;15:607-20.
Mao Z, Bozzella M, Seluanov A. DNA repair by nonhomologous end joining and homologous recombination during cell cycle in humans. Cell Cycle 2008;7:2902-6.
Mazin AV, Alexeev AA, Kowalczykowski SC. A novel function of rad54 protein. Stabilization of the Rad51 nucleoprotein filament. J Biol Chem 2003;278:14029-36.
Compton SA, Ozgur S, Griffith JD. Ring shaped Rad51 paralog protein complexes bind holiday junctions and replication forks as visualized by electron microscopy. J Biol Chem 2010;285:13349-56.
Wyatt HD, West SC. Holiday junction resolvases. Cold Spring Harb Perspect Biol 2014;6:A023192.
Moynahan ME, Chiu JW, Koller BH, Jasin M. Brca1 controls homology-directed DNA repair. Mol Cell 1999;4:511-8.
Torres-Rosell J, Sunjevaric I, De Picoli G, Sacher M, Eckert-Boulet N, Reid R et al
. The smc5-smc6 and SUMO modification of Rad52 regulates recombinational repair at the ribosomal gene locus. Nat Cell Biol 2007;9:923-31.
Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res 2008;18:85-98.
Goodenberger M, Lindor NM. Lynch syndrome and MYH-associated polyposis: Review and testing strategy. J Clin Gastroenterol 2011;45:488-500.
Mirzaee V, Molaei M, Shalmani HM, Zali MR. Helicobacter pylori
infection and expression of DNA mismatch repair proteins. World J Gastroenterol 2008;14:6717-21.
Watson M, Barret A, Spence R, Twelves C. Oncology. 2nd
ed. NewYork: Oxford Core Texts; 2006. p. 133-43.
Boulton SJ. DNA repair: Decision at break the break point. Nature 2010;465:301-2.
Seemanova E, Jarolim P, Seeman P, Varon R, Digweed M, Swift M, et al
. Cancer risk of heterozygotes with NBN founder mutation. J Natl Cancer Inst 2007;99:1875-80.
van Steeg H, Kraemer KH. Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. Mol Med Today 1999;5:86-94.
Sugasawa K. Xeroderma pigmentosum genes: Functions inside and outside DNA repair. Carcinogenesis 2008;29:455-65.
[Figure 1], [Figure 2], [Figure 3]