DNA repair-deficiency disorder

DNA repair-deficiency disorder
Classification and external resources
MeSH D049914

A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

DNA repair defects can cause both an accelerated aging disease and an increased risk of cancer.

DNA repair defects and accelerated aging

DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely. Because the accelerated aging diseases display different aspects of aging, but never every aspect, they are often called segmental progerias by biogerontologists.


Some of the examples include:

DNA repair defects distinguished from "accelerated aging"

Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (often some of both).[7] But elimination of any gene essential for base excision repair kills the embryo—it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging").[8] Rothmund-Thomson syndrome and xeroderma pigmentosum display symptoms dominated by vulnerability to cancer, whereas progeria and Werner syndrome show the most features of "accelerated aging". Hereditary nonpolyposis colorectal cancer (HNPCC) is very often caused by a defective MSH2 gene leading to defective mismatch repair, but displays no symptoms of "accelerated aging".[9] On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer[10] Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging".[11] (Also see the "DNA damage theory of aging" for a discussion of the evidence that DNA damage is the primary underlying cause of aging.)

Debate concerning "accelerated aging"

Some biogerontologists question that such a thing as "accelerated aging" actually exists, at least partly on the grounds that all of the so-called accelerated aging diseases are segmental progerias. Many disease conditions such as diabetes, high blood pressure, etc., are associated with increased mortality. Without reliable biomarkers of aging it is hard to support the claim that a disease condition represents more than accelerated mortality.[12]

Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage.[7] The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging".[13] Such conditions, it is argued, are readily distinguishable from genetic diseases associated with increased mortality, but not associated with an aging phenotype, such as cystic fibrosis and sickle cell anemia. It is further argued that segmental aging phenotype is a natural part of aging insofar as genetic variation leads to some people being more disposed than others to aging-associated diseases such as cancer and Alzheimer's disease.[14]

DNA repair defects and increased cancer risk

Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer.[15] When a mutation is present in a DNA repair gene, the repair gene will either not be expressed or be expressed in an altered form. Then the repair function will likely be deficient, and, as a consequence, damages will tend to accumulate. Such DNA damages can cause errors during DNA synthesis leading to mutations, some of which may give rise to cancer. Germ-line DNA repair mutations that increase the risk of cancer are listed in the Table.

Inherited DNA repair gene mutations that increase cancer risk
DNA repair gene Protein Repair pathways affected Cancers with increased risk
breast cancer 1 & 2 BRCA1 BRCA2 HRR of double strand breaks and daughter strand gaps[16] breast, ovarian [17]
ataxia telangiectasia mutated ATM Different mutations in ATM reduce HRR, SSA or NHEJ [18] leukemia, lymphoma, breast [18][19]
Nijmegen breakage syndrome NBS (NBN) NHEJ [20] lymphoid cancers [20]
MRE11A MRE11 HRR and NHEJ [21] breast [22]
Bloom syndrome BLM (helicase) HRR [23] leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus [24]
WRN WRN HRR, NHEJ, long patch BER [25] soft tissue sarcoma, colorectal, skin, thyroid, pancreas [26]
RECQL4 RECQ4 Helicase likely active in HRR [27] basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma [28]
Fanconi anemia genes FANCA,B,C,D1,D2,E,F,G,I,J,L,M,N FANCA etc. HRR and TLS [29] leukemia, liver tumors, solid tumors many areas [30]
XPC, XPE (DDB2) XPC, XPE Global genomic NER, repairs damage in both transcribed and untranscribed DNA [31][32] skin cancer (melanoma and non-melanoma) [31][32]
XPA, XPB, XPD, XPF, XPG XPA XPB XPD XPF XPG Transcription coupled NER repairs the transcribed strands of transcriptionally active genes [33] skin cancer (melanoma and non-melanoma) [33]
XPV (also called polymerase H) XPV (POLH) Translesion synthesis (TLS) [34] skin cancers (basal cell, squamous cell, melanoma) [34]
mutS (E. coli) homolog 2, mutS (E. coli) homolog 6, mutL (E. coli) homolog 1,

postmeiotic segregation increased 2 (S. cerevisiae)

MSH2 MSH6 MLH1 PMS2 MMR [35] colorectal, endometrial [35]
mutY homolog (E. coli) MUTYH BER of A paired with 8-oxo-dG [36] colon [36]
TP53 P53 Direct role in HRR, BER, NER and acts in DNA damage response[37] for those pathways and for NHEJ and MMR [38] sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas [39]
NTHL1 NTHL1 BER for Tg, FapyG, 5-hC, 5-hU in dsDNA[40] Colon cancer, endometrial cancer, duodenal cancer, basal-cell carcinoma[41]

See also


  1. Biton S, Dar I, Mittelman L, Pereg Y, Barzilai A, Shiloh Y (June 2006). "Nuclear ataxia-telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells". J. Biol. Chem. 281 (25): 17482–91. doi:10.1074/jbc.M601895200. PMID 16627474.
  2. Manju K, Muralikrishna B, Parnaik VK (July 2006). "Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci". J. Cell. Sci. 119 (Pt 13): 2704–14. doi:10.1242/jcs.03009. PMID 16772334.
  3. Scaffidi P, Misteli T (May 2006). "Lamin A-dependent nuclear defects in human aging". Science. 312 (5776): 1059–63. doi:10.1126/science.1127168. PMC 1855250Freely accessible. PMID 16645051.
  4. Brosh RM, Bohr VA (2007). "Human premature aging, DNA repair and RecQ helicases". Nucleic Acids Res. 35 (22): 7527–44. doi:10.1093/nar/gkm1008. PMC 2190726Freely accessible. PMID 18006573.
  5. Kitao S, Shimamoto A, Goto M, et al. (May 1999). "Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome". Nat. Genet. 22 (1): 82–4. doi:10.1038/8788. PMID 10319867.
  6. Kleijer WJ, Laugel V, Berneburg M, et al. (May 2008). "Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy". DNA Repair (Amst.). 7 (5): 744–50. doi:10.1016/j.dnarep.2008.01.014. PMID 18329345.
  7. 1 2 Best,BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328.
  8. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J (February 2003). "Aging and genome maintenance: lessons from the mouse?". Science. 299 (5611): 1355–9. doi:10.1126/science.1079161. PMID 12610296.
  9. Mazurek A, Berardini M, Fishel R (March 2002). "Activation of human MutS homologs by 8-oxo-guanine DNA damage". J. Biol. Chem. 277 (10): 8260–6. doi:10.1074/jbc.M111269200. PMID 11756455.
  10. Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009 Oct 8;361(15):1475-85.
  11. Rass U, Ahel I, West SC (September 2007). "Defective DNA repair and neurodegenerative disease". Cell. 130 (6): 991–1004. doi:10.1016/j.cell.2007.08.043. PMID 17889645.
  12. Miller RA (April 2004). "'Accelerated aging': a primrose path to insight?". Aging Cell. 3 (2): 47–51. doi:10.1111/j.1474-9728.2004.00081.x. PMID 15038817.
  13. Hasty P, Vijg J (April 2004). "Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity". Aging Cell. 3 (2): 55–65. doi:10.1111/j.1474-9728.2004.00082.x. PMID 15038819.
  14. Hasty P, Vijg J (April 2004). "Rebuttal to Miller: 'Accelerated aging': a primrose path to insight?'". Aging Cell. 3 (2): 67–9. doi:10.1111/j.1474-9728.2004.00087.x. PMID 15038820.
  15. Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002 Jun;511(2):145-78. Review.
  16. Nagaraju G, Scully R (2007). "Minding the gap: the underground functions of BRCA1 and BRCA2 at stalled replication forks". DNA Repair (Amst.). 6 (7): 1018–31. doi:10.1016/j.dnarep.2007.02.020. PMC 2989184Freely accessible. PMID 17379580.
  17. Lancaster JM, Powell CB, Chen LM, Richardson DL (2015). "Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions". Gynecol. Oncol. 136 (1): 3–7. doi:10.1016/j.ygyno.2014.09.009. PMID 25238946.
  18. 1 2 Keimling M, Volcic M, Csernok A, Wieland B, Dörk T, Wiesmüller L (2011). "Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways". FASEB J. 25 (11): 3849–60. doi:10.1096/fj.11-185546. PMID 21778326.
  19. Thompson LH, Schild D (2002). "Recombinational DNA repair and human disease". Mutat. Res. 509 (1-2): 49–78. doi:10.1016/s0027-5107(02)00224-5. PMID 12427531.
  20. 1 2 Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M (2012). "Nijmegen breakage syndrome (NBS)". Orphanet J Rare Dis. 7: 13. doi:10.1186/1750-1172-7-13. PMC 3314554Freely accessible. PMID 22373003.
  21. Rapp A, Greulich KO (2004). "After double-strand break induction by UV-A, homologous recombination and nonhomologous end joining cooperate at the same DSB if both systems are available". J. Cell. Sci. 117 (Pt 21): 4935–45. doi:10.1242/jcs.01355. PMID 15367581.
  22. Bartkova J, Tommiska J, Oplustilova L, Aaltonen K, Tamminen A, Heikkinen T, Mistrik M, Aittomäki K, Blomqvist C, Heikkilä P, Lukas J, Nevanlinna H, Bartek J (2008). "Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene". Mol Oncol. 2 (4): 296–316. doi:10.1016/j.molonc.2008.09.007. PMID 19383352.
  23. Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC (2008). "Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair". Proc. Natl. Acad. Sci. U.S.A. 105 (44): 16906–11. doi:10.1073/pnas.0809380105. PMC 2579351Freely accessible. PMID 18971343.
  24. German J (1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". Am. J. Hum. Genet. 21 (2): 196–227. PMC 1706430Freely accessible. PMID 5770175.
  25. Bohr VA (2005). "Deficient DNA repair in the human progeroid disorder, Werner syndrome". Mutat. Res. 577 (1-2): 252–9. doi:10.1016/j.mrfmmm.2005.03.021. PMID 15916783.
  26. Monnat RJ (2010). "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39. doi:10.1016/j.semcancer.2010.10.002. PMC 3040982Freely accessible. PMID 20934517.
  27. Singh DK, Ahn B, Bohr VA (2009). "Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging". Biogerontology. 10 (3): 235–52. doi:10.1007/s10522-008-9205-z. PMC 2713741Freely accessible. PMID 19083132.
  28. Anbari KK, Ierardi-Curto LA, Silber JS, Asada N, Spinner N, Zackai EH, Belasco J, Morrissette JD, Dormans JP (2000). "Two primary osteosarcomas in a patient with Rothmund-Thomson syndrome". Clin. Orthop. Relat. Res. 378: 213–23. doi:10.1097/00003086-200009000-00032. PMID 10986997.
  29. Thompson LH, Hinz JM (2009). "Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights". Mutat. Res. 668 (1-2): 54–72. doi:10.1016/j.mrfmmm.2009.02.003. PMC 2714807Freely accessible. PMID 19622404.
  30. Alter BP (2003). "Cancer in Fanconi anemia, 1927-2001". Cancer. 97 (2): 425–40. doi:10.1002/cncr.11046. PMID 12518367.
  31. 1 2 Lehmann AR, McGibbon D, Stefanini M (2011). "Xeroderma pigmentosum". Orphanet J Rare Dis. 6: 70. doi:10.1186/1750-1172-6-70. PMC 3221642Freely accessible. PMID 22044607.
  32. 1 2 Oh KS, Imoto K, Emmert S, Tamura D, DiGiovanna JJ, Kraemer KH (2011). "Nucleotide excision repair proteins rapidly accumulate but fail to persist in human XP-E (DDB2 mutant) cells". Photochem. Photobiol. 87 (3): 729–33. doi:10.1111/j.1751-1097.2011.00909.x. PMC 3082610Freely accessible. PMID 21388382.
  33. 1 2 Menck CF, Munford V (2014). "DNA repair diseases: What do they tell us about cancer and aging?". Genet. Mol. Biol. 37 (1 Suppl): 220–33. doi:10.1590/s1415-47572014000200008. PMC 3983582Freely accessible. PMID 24764756.
  34. 1 2 Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert C, Kannouche P, Soufir N, Sarasin A (2014). "Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations". Hum. Mutat. 35 (1): 117–28. doi:10.1002/humu.22462. PMID 24130121.
  35. 1 2 Meyer LA, Broaddus RR, Lu KH (2009). "Endometrial cancer and Lynch syndrome: clinical and pathologic considerations". Cancer Control. 16 (1): 14–22. PMC 3693757Freely accessible. PMID 19078925.
  36. 1 2 Markkanen E, Dorn J, Hübscher U (2013). "MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA". Front Genet. 4: 18. doi:10.3389/fgene.2013.00018. PMC 3584444Freely accessible. PMID 23450852.
  37. Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
  38. Viktorsson K, De Petris L, Lewensohn R (2005). "The role of p53 in treatment responses of lung cancer". Biochem. Biophys. Res. Commun. 331 (3): 868–80. doi:10.1016/j.bbrc.2005.03.192. PMID 15865943.
  39. Testa JR, Malkin D, Schiffman JD (2013). "Connecting molecular pathways to hereditary cancer risk syndromes". Am Soc Clin Oncol Educ Book. 33: 81–90. doi:10.1200/EdBook_AM.2013.33.81. PMID 23714463.
  40. Krokan HE, Bjørås M (2013). "Base excision repair". Cold Spring Harb Perspect Biol. 5 (4): a012583. doi:10.1101/cshperspect.a012583. PMC 3683898Freely accessible. PMID 23545420.
  41. Kuiper RP, Hoogerbrugge N (2015). "NTHL1 defines novel cancer syndrome". Oncotarget. 6 (33): 34069–70. doi:10.18632/oncotarget.5864. PMC 4741436Freely accessible. PMID 26431160.
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