DNA repair-deficiency disorder

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

Contents

DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both.

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.[ citation needed ]

Human disorders with accelerated aging

Examples

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).
ProteinPathwayDescription
ATR Nucleotide excision repair [1] deletion 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 spermatogenesis [2]
DNA-PKcs Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [3] [4] higher level of DNA damage persistence [5]
ERCC1 Nucleotide excision repair, Interstrand cross link repair [6] deficient transcription coupled NER with time-dependent accumulation of transcription-blocking damages; [7] mouse life span reduced from 2.5 years to 5 months; [8] ) Ercc1−/− mice are leukopenic and thrombocytopenic, and there is extensive adipose transformation of the bone marrow, hallmark features of normal aging in mice [6]
ERCC2 (XPD) Nucleotide excision repair (also transcription as part of TFIIH)some mutations in ERCC2 cause Cockayne syndrome in which patients have segmental progeria with reduced stature, intellectual disability, cachexia (loss of subcutaneous fat tissue), sensorineural deafness, retinal degeneration, and calcification of the central nervous system; other mutations in ERCC2 cause trichothiodystrophy in which patients have segmental progeria with brittle hair, short stature, progressive cognitive impairment and abnormal face shape; still other mutations in ERCC2 cause xeroderma pigmentosum (without a progeroid syndrome) and with extreme sun-mediated skin cancer predisposition [9]
ERCC4 (XPF) Nucleotide excision repair, Interstrand cross link repair, Single-strand annealing, Microhomology-mediated end joining [6] mutations in ERCC4 cause symptoms of accelerated aging that affect the neurologic, hepatobiliary, musculoskeletal, and hematopoietic systems, and cause an old, wizened appearance, loss of subcutaneous fat, liver dysfunction, vision and hearing loss, chronic kidney disease, muscle wasting, osteopenia, kyphosis and cerebral atrophy [6]
ERCC5 (XPG) Nucleotide excision repair, [10] Homologous recombinational repair, [11] Base excision repair [12] [13] mice with deficient ERCC5 show loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months
ERCC6 (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, [14] deficient transcription coupled NER with accumulation of unrepaired DNA damages, [15] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines [15]
ERCC8 (Cockayne syndrome A or CS-A) Nucleotide excision repair [especially transcription coupled repair (TC-NER) and interstrand crosslink repair]premature aging features with shorter life span and photosensitivity, [14] deficient transcription coupled NER with accumulation of unrepaired DNA damages, [15] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines [15]
GTF2H5 (TTDA) Nucleotide excision repair deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein [16] with retarded repair of 6-4-photoproducts [17]
Ku70 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [18] persistent foci of DNA double-strand break repair proteins [19]
Ku80 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [20] defective repair of spontaneous DNA damage [18]
Lamin A Non-homologous end joining, Homologous recombination increased DNA damage and chromosome aberrations; progeria; aspects of premature aging; altered expression of numerous DNA repair factors [21]
NRMT1 Nucleotide excision repair [22] mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration [23]
RECQL4 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [24] mutations in RECQL4 cause Rothmund-Thomson syndrome, with alopecia, sparse eyebrows and lashes, cataracts and osteoporosis [24]
SIRT6 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [25] SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes [26]
SIRT7 Non-homologous end joining mice 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 joining [27]
Werner syndrome helicase Homologous recombination, [28] [29] Non-homologous end joining, [30] Base excision repair, [31] [32] Replication arrest recovery [33] shorter lifespan, earlier onset of aging related pathologies, genome instability [34] [35]
ZMPSTE24 Homologous recombination lack 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 [36]

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). [37] 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"). [38] 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". [39] On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer [40] Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging". [41] (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. [42]

Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage. [37] The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". [43] 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. [44]

DNA repair defects and increased cancer risk

Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. [45] 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 geneProteinRepair pathways affectedCancers with increased risk
breast cancer 1 & 2 BRCA1 BRCA2 HRR of double strand breaks and daughter strand gaps [46] breast, ovarian [47]
ataxia telangiectasia mutated ATM Different mutations in ATM reduce HRR, SSA or NHEJ [48] leukemia, lymphoma, breast [48] [49]
Nijmegen breakage syndrome NBS (NBN) NHEJ [50] lymphoid cancers [50]
MRE11A MRE11 HRR and NHEJ [51] breast [52]
Bloom syndrome BLM (helicase)HRR [53] leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus [54]
WRN WRNHRR, NHEJ, long patch BER [55] soft tissue sarcoma, colorectal, skin, thyroid, pancreas [56]
RECQL4 RECQ4Helicase likely active in HRR [57] basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma [58]
Fanconi anemia genes FANCA, B, C, D1, D2, E, F, G, I, J, L, M, NFANCA etc.HRR and TLS [59] leukemia, liver tumors, solid tumors many areas [60]
XPC, XPE (DDB2)XPC, XPE Global genomic NER, repairs damage in both transcribed and untranscribed DNA [61] [62] skin cancer (melanoma and non-melanoma) [61] [62]
XPA, XPB, XPD, XPF, XPG XPA XPB XPD XPF XPG Transcription coupled NER repairs the transcribed strands of transcriptionally active genes [63] skin cancer (melanoma and non-melanoma) [63]
XPV (also called polymerase H)XPV (POLH) Translesion synthesis (TLS) [64] skin cancers (basal cell, squamous cell, melanoma) [64]
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 [65] colorectal, endometrial [65]
mutY homolog (E. coli) MUTYH BER of A paired with 8-oxo-dG [66] colon [66]
TP53 P53Direct role in HRR, BER, NER and acts in DNA damage response [67] for those pathways and for NHEJ and MMR [68] sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas [69]
NTHL1 NTHL1BER for Tg, FapyG, 5-hC, 5-hU in dsDNA [70] Colon cancer, endometrial cancer, duodenal cancer, basal-cell carcinoma [71]

See also

Related Research Articles

<span class="mw-page-title-main">Progeria</span> Genetic disorder that causes early aging

Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome or Hutchinson–Gilford progeroid syndrome (HGPS). A single gene mutation is responsible for causing progeria. The affected gene, known as lamin A (LMNA), makes a protein necessary for holding the cell nucleus together. When this gene mutates, an abnormal form of lamin A protein called progerin is produced. Progeroid syndromes are a group of diseases that cause individuals to age faster than usual, leading to them appearing older than they actually are. People born with progeria typically live until their mid- to late-teens or early twenties. Severe cardiovascular complications usually develop by puberty, later on resulting in death.

<span class="mw-page-title-main">Werner syndrome</span> Medical condition

Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria", is a rare, autosomal recessive disorder which is characterized by the appearance of premature aging.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">Xeroderma pigmentosum</span> Medical condition

Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun-exposed areas, dry skin and changes in skin pigmentation. Nervous system problems, such as hearing loss, poor coordination, loss of intellectual function and seizures, may also occur. Complications include a high risk of skin cancer, with about half having skin cancer by age 10 without preventative efforts, and cataracts. There may be a higher risk of other cancers such as brain cancers.

<span class="mw-page-title-main">Nucleotide excision repair</span> DNA repair mechanism

Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals, radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.

<span class="mw-page-title-main">Werner syndrome helicase</span> Enzyme found in humans

Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

<span class="mw-page-title-main">XPB</span> Mammalian protein found in Homo sapiens

XPB is an ATP-dependent DNA helicase in humans that is a part of the TFIIH transcription factor complex.

<span class="mw-page-title-main">ERCC2</span> Mammalian protein found in humans

TFIIH subunit XPD is a protein that in humans is encoded by the ERCC2 gene. It is a component of the general transcription and DNA repair factor IIH (TFIIH) core complex involved in transcription-coupled nucleotide excision repair.

<span class="mw-page-title-main">Prelamin-A/C</span> Filament protein

Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.

<span class="mw-page-title-main">XPC (gene)</span> Protein-coding gene in the species Homo sapiens

Xeroderma pigmentosum, complementation group C, also known as XPC, is a protein which in humans is encoded by the XPC gene. XPC is involved in the recognition of bulky DNA adducts in nucleotide excision repair. It is located on chromosome 3.

<span class="mw-page-title-main">ERCC6</span> Gene of the species Homo sapiens

DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.

<span class="mw-page-title-main">ERCC5</span> Protein-coding gene in the species Homo sapiens

DNA repair protein complementing XP-G cells is a protein that in humans is encoded by the ERCC5 gene.

<span class="mw-page-title-main">ERCC4</span> Protein-coding gene in the species Homo sapiens

ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

<span class="mw-page-title-main">ERCC8</span> Protein-coding gene in humans

DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.

<span class="mw-page-title-main">GTF2H5</span> Protein-coding gene in the species Homo sapiens

General transcription factor IIH subunit 5 is a protein that in humans is encoded by the GTF2H5 gene.

ZMPSTE24 is a human gene. The protein encoded by this gene is a metallopeptidase. It is involved in the processing of lamin A. Defects in the ZMPSTE24 gene lead to similar laminopathies as defects in lamin A, because the latter is a substrate for the former. In humans, a mutation abolishing the ZMPSTE24 cleavage site in prelamin A causes a progeroid disorder. Failure to correctly process prelamin A leads to deficient ability to repair DNA double-strand breaks.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term progeroid syndrome does not necessarily imply progeria, which is a specific type of progeroid syndrome.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

Jan Vijg is the Lola and Saul Kramer Chairperson in Molecular Genetics at the Department of Genetics at the Albert Einstein College of Medicine, New York City, United States. Prior to this appointment, he was a professor at the Buck Institute for Research on Aging.

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