DNA repair-deficiency disorder

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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[edit]

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"[edit]

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"[edit]

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[edit]

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 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]

See also[edit]


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External links[edit]