DNA repair-deficiency disorder

A DNA repair deficiency disorder is a medical condition due to reduced functionality of DNA repair. DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.

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 examples of DNA repair defects causing progeroid syndromes in humans or mice are shown in Table 1. + Table 1. DNA repair proteins that, when deficient, cause features of accelerated aging (segmental progeria). ProteinPathwayDescriptionATRNucleotide excision repairdeletion of ATR in adult mice leads to a number of disorders including hair loss and graying, kyphosis, osteoporosis, premature involution of the thymus, fibrosis of the heart and kidney and decreased spermatogenesisDNA PKcsNon homologous end joiningshorter lifespan, earlier onset of aging related pathologies; higher level of DNA damage persistenceERCC1Nucleotide excision repair, Interstrand cross link repairdeficient transcription coupled NER with time dependent accumulation of transcription blocking damages; mouse life span reduced from 2.5 years to 5 months;) Ercc1−/− mice are leukopenic and thrombocytopenic, and there is extensive adipose transformation of the bone marrow, hallmark features of normal aging in miceERCC4 (XPF)Nucleotide excision repair, Interstrand cross link repair, Single strand annealing, Microhomology mediated end joining Homologous recombinational repair, Base excision repairmice with deficient ERCC5 show loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 monthsERCC6 (Cockayne syndrome B or CS B)Nucleotide excision repair [especially transcription coupled repair (TC NER) and interstrand crosslink repair]premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8 oxoguanine, 5 hydroxycytosine and cyclopurines with retarded repair of 6 4 photoproductsKu70Non homologous end joiningshorter lifespan, earlier onset of aging related pathologies; persistent foci of DNA double strand break repair proteinsKu80Non homologous end joiningshorter lifespan, earlier onset of aging related pathologies; defective repair of spontaneous DNA damageNRMT1Nucleotide excision repairmutation in NRMT1 causes decreased body size, female specific infertility, kyphosis, decreased mitochondrial function, and early onset liver degenerationRECQL4Base excision repair, Nucleotide excision repair, Homologous recombination, Non homologous end joining mutations in RECQL4 cause Rothmund Thomson syndrome, with alopecia, sparse eyebrows and lashes, cataracts and osteoporosisSIRT6 deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging associated degenerative processesSIRT7Non homologous end joiningmice defective in SIRT7 show phenotypic and molecular signs of accelerated aging such as premature pronounced curvature of the spine, reduced life span, and reduced non homologous end joiningWerner syndrome helicaseHomologous recombination, Non homologous end joining,Base excision repair, Replication arrest recoveryshorter lifespan, earlier onset of aging related pathologies, genome instabilityZMPSTE24 Homologous recombinationlack of Zmpste24 prevents lamin A formation and causes progeroid phenotypes in mice and humans, increased DNA damage and chromosome aberrations, sensitivity to DNA damaging agents and deficiency in homologous recombination

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.)

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. 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.

Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. 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 riskDNA repair geneProteinRepair pathways affectedCancers with increased riskbreast cancer 1 & 2BRCA1 BRCA2HRR of double strand breaks and daughter strand gapsbreast, ovarian ataxia telangiectasia mutatedATMDifferent mutations in ATM reduce HRR, SSA or NHEJ leukemia, lymphoma, breast Nijmegen breakage syndromeNBS (NBN)NHEJ lymphoid cancers breast Bloom syndrome BLM (helicase)HRR leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus WRNWRNHRR, NHEJ, long patch BER soft tissue sarcoma, colorectal, skin, thyroid, pancreas RECQL4RECQ4Helicase likely active in HRR basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma Fanconi anemia genes FANCA, B, C, D1, D2, E, F, G, I, J, L, M, NFANCA etc. HRR and TLS leukemia, liver tumors, solid tumors many areas XPC, XPE (DDB2)XPC, XPEGlobal genomic NER, repairs damage in both transcribed and untranscribed DNA skin cancer (melanoma and non melanoma) skin cancer (melanoma and non melanoma) skin cancers (basal cell, squamous cell, melanoma) colorectal, endometrial colon for those pathways and for NHEJ and MMR sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas NTHL1NTHL1BER for Tg, FapyG, 5 hC, 5 hU in dsDNAColon cancer, endometrial cancer, duodenal cancer, basal cell carcinoma