DNA repair-deficiency disorder
|DNA repair-deficiency disorder|
|Classification and external resources|
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.
- 1 DNA repair defects and accelerated aging
- 2 DNA repair defects and increased cancer risk
- 3 See also
- 4 References
- 5 External links
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:
- Ataxia telangiectasia
- Bloom syndrome
- Cockayne's syndrome
- Fanconi's anaemia
- Progeria (Hutchinson-Gilford Progeria syndrome)
- Rothmund-Thomson syndrome
- Werner syndrome
- Xeroderma pigmentosum
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). 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"). 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". On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging". (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.
Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage. The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". 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.
DNA repair defects and increased cancer risk
Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. If there is a mutation in a DNA repair gene, the repair gene will either not be expressed or expressed in a mutated form. Consequently the repair function will be deficient or altered, and damages will accumulate. Such DNA damages, if not repaired, cause errors during DNA synthesis leading to mutations that can give rise to cancer. The abbreviated names of the most well studied DNA repair genes (for which a mutation results in an increased risk of cancer) are followed by an abbreviated name of the repair pathway affected, and by the tissue in which cancer develops when the gene is mutated. Below the list is shown the full name of each gene and the affected pathway(s).
List of inherited DNA repair gene mutations that increase cancer risk
- BRCA1, BRCA2
- Lymphoid malignancies
- RECQ4 (RECQL4) causing Rothmund-Thomson syndrome (RTS), RAPADILINO syndrome or Baller Gerold syndrome
- likely HRR
- FANCA, FANCB, FANCC, FANCDl, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN
- XPC, XPE(DDB2)
- XPA, XPB, XPD, XPF, XPG
- hMSH2, hMSH6, hMLH1, hPMS2
Names of genes: BRCAl, BRCA2 breast Cancer 1 and 2; ATM Ataxia telangiectasia mutated; NBS Nijmegen breakage syndrome; MRE11 meiotic recombination 11; BLM Bloom's syndrome; WRN Werner syndrome; RECQ4 (RECQL4) ATP-dependent DNA helicase Q4; FANCA, FANCB, FANCC, FANCDl, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN mutations in any of these 13 genes give rise to Fanconi anemia; XPC xeroderma pigmentosa C; XPE(DDB2) DNA damage-binding protein 2, the smaller subunit of a heterodimeric protein implicated in the etiology of xeroderma pigmentosum group E; XPA, XPB, XPD, XPF, XPG mutations in any of these 4 genes give rise to xeroderma pigmentosa; XPV(POLH) mutation in polymerase H gives rise to xeroderma pigmentosa; hMSH2, hMSH6, hMLH1, hPMS2 mutS (E. coli) homolog 2, mutS (E. coli) homolog 6, mutL (E. coli) homolog 1, postmeiotic segregation increased 2 (S. cerevisiae); MUTYH MutY homolog (E. coli). Names of DNA repair pathways: HRR homologous recombinational repair; NHEJ non-homologous end joining; DSBR (HDR) double strand break repair (homology directed repair); TLS trans lesion synthesis; NER(GGR type) nucleotide excision repair (global genome repair type); NER(TCR type) nucleotide excision repair (transcription coupled repair type); MMR mismatch repair; BER of A base excision repair of adenine (mispaired)...
- 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.
- 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.
- 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 1855250. PMID 16645051.
- 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 2190726. PMID 18006573.
- 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.
- 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.
- Best,BP (2009). "Nuclear DNA damage as a direct cause of aging". Rejuvenation Research 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328.
- 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.
- 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.
- Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009 Oct 8;361(15):1475-85.
- 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.
- 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.
- 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.
- 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.
- 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.
- Nagaraju G, Scully R. Minding the gap: the underground functions of BRCA1 and BRCA2 at stalled replication forks. DNA Repair (Amst). 2007 Jul 1;6(7):1018-31.
- Lancaster JM, Powell CB, Kauff ND, Cass I, Chen LM, Lu KH, Mutch DG, Berchuck A, Karlan BY, Herzog TJ; Society of Gynecologic Oncologists Education Committee. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2007 Nov;107(2):159-62.
- Keimling M, Volcic M, Csernok A, Wieland B, Dörk T, Wiesmüller L. Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways. FASEB J. 2011 Nov;25(11):3849-60
- Thompson LH, Schild D. Recombinational DNA repair and human disease. Mutat Res. 2002 Nov 30;509(1-2):49-78. Review.
- Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012 Feb 28;7:13..
- 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. Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene. Mol Oncol. 2008 Dec;2(4):296-316.
- Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC. Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16906-11
- German J. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet. 1997 Jan;93(1):100-6.
- Chen L, Huang S, Lee L, Davalos A, Schiestl RH, Campisi J, Oshima J. WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging Cell. 2003 Aug;2(4):191-9.
- Ahn B, Lee JW, Jung H, Beck G, Bohr VA. Mechanism of Werner DNA helicase: POT1 and RPA stimulates WRN to unwind beyond gaps in the translocating strand. PLoS One. 2009;4(3):e4673.
- Chun SG, Shaeffer DS, Bryant-Greenwood PK. The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging. Hawaii Med J. 2011 Mar;70(3):52-5.
- Singh DK, Ahn B, Bohr VA. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology. 2009 Jun;10(3):235-52.
- Anbari KK, Ierardi-Curto LA, Silber JS, Asada N, Spinner N, Zackai EH, Belasco J, Morrissette JD, Dormans JP. Two primary osteosarcomas in a patient with Rothmund-Thomson syndrome. Clin Orthop Relat Res. 2000 Sep;(378):213-23.
- Thompson LH, Hinz JM. Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights. Mutat Res. 2009 Jul 31;668(1-2):54-72.
- Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer. 2003 Jan 15;97(2):425-40.
- Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011 Nov 1;6:70.
- Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005 May;128(5):1160-71.
- Manchanda R, Menon U, Michaelson-Cohen R, Beller U, Jacobs I. Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective. Curr Opin Obstet Gynecol. 2009 Feb;21(1):31-8.
- David SS, O'Shea VL, Kundu S. Base-excision repair of oxidative DNA damage. Nature. 2007 Jun 21;447(7147):941-50.
- Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, Haile R, Hopper JL, LeMarchand L, Lindor N, Parfrey P, Potter J, Younghusband B, Gallinger S. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009 Apr;136(4):1251-60.
- BRCA - Companion Reviews and Search Terms
- BRCA1 - Companion Reviews and Search Terms
- BRCA2 - Companion Reviews and Search Terms
- ATM - Companion Reviews and Search Terms
- NBS1 - Companion Reviews and Search Terms
- Bloom s syndrome - Companion Reviews and Search Terms
- Fanconi s anemia - Companion Reviews and Search Terms
- WRN - Companion Reviews and Search Terms
- RECQ- Companion Reviews and Search Terms
- RECQL4 - Companion Reviews and Search Terms
- FANCJ - Companion Reviews and Search Terms
- FANCM - Companion Reviews and Search Terms
- FANCN - Companion Reviews and Search Terms
- XPB - Companion Reviews and Search Terms
- XPD - Companion Reviews and Search Terms
- XPG - Companion Reviews and Search Terms
- MSH6 - Companion Reviews and Search Terms
- MUTYH - Companion Reviews and Search Terms
- DNA repair and toxicology - Companion Reviews and Search Terms
- Neoplasia inherited - Companion Reviews and Search Terms
- Neoplasia carcinogenesis - Companion Reviews and Search Terms
- Segmental Progeria