Open Access Articles- Top Results for DNA repair-deficiency disorder

DNA repair-deficiency disorder

DNA repair-deficiency disorder
Classification and external resources
NCI DNA repair-deficiency disorder
Patient UK DNA repair-deficiency disorder
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] 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

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)...

See also


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