Medicine:DNA repair-deficiency disorder

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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 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.

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).
Protein Pathway Description
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
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[6]
ERCC4 (XPF) Nucleotide excision repair, Interstrand cross link repair, Single-strand annealing, Microhomology-mediated end joining[7] 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[7]
ERCC5 (XPG) Nucleotide excision repair,[8] Homologous recombinational repair,[9] Base excision repair[10][11] 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,[12] deficient transcription coupled NER with accumulation of unrepaired DNA damages,[13] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines[13]
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,[12] deficient transcription coupled NER with accumulation of unrepaired DNA damages,[13] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines[13]
GTF2H5 (TTDA) Nucleotide excision repair deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein[14] with retarded repair of 6-4-photoproducts[15]
Ku70 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies;[16] persistent foci of DNA double-strand break repair proteins[17]
Ku80 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies;[18] defective repair of spontaneous DNA damage[16]
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[19]
NRMT1 Nucleotide excision repair[20] mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration[21]
RECQL4 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining[22] mutations in RECQL4 cause Rothmund-Thomson syndrome, with alopecia, sparse eyebrows and lashes, cataracts and osteoporosis[22]
SIRT6 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [23] SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes[24]
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[25]
Werner syndrome helicase shorter lifespan, earlier onset of aging related pathologies, genome instability[26][27]
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[28]

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).[29] 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").[30] 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".[31] On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer[32] Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging".[33] (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.[34]

Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage.[29] The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging".[35] 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.[36]

DNA repair defects and increased cancer risk

Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer.[37] 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 gene Protein Repair pathways affected Cancers with increased risk
breast cancer 1 & 2 BRCA1 BRCA2 HRR of double strand breaks and daughter strand gaps[38] breast, ovarian [39]
ataxia telangiectasia mutated ATM Different mutations in ATM reduce HRR, SSA or NHEJ [40] leukemia, lymphoma, breast [40][41]
Nijmegen breakage syndrome NBS (NBN) NHEJ [42] lymphoid cancers [42]
MRE11A MRE11 HRR and NHEJ [43] breast [44]
Bloom syndrome BLM (helicase) HRR [45] leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stomach, tonsil, larynx, uterus [46]
WRN WRN HRR, NHEJ, long patch BER [47] soft tissue sarcoma, colorectal, skin, thyroid, pancreas [48]
RECQL4 RECQ4 Helicase likely active in HRR [49] basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma [50]
Fanconi anemia genes FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N FANCA etc. HRR and TLS [51] leukemia, liver tumors, solid tumors many areas [52]
XPC, XPE (DDB2) XPC, XPE Global genomic NER, repairs damage in both transcribed and untranscribed DNA [53][54] skin cancer (melanoma and non-melanoma) [53][54]
XPA, XPB, XPD, XPF, XPG XPA XPB XPD XPF XPG Transcription coupled NER repairs the transcribed strands of transcriptionally active genes [55] skin cancer (melanoma and non-melanoma) [55]
XPV (also called polymerase H) XPV (POLH) Translesion synthesis (TLS) [56] skin cancers (basal cell, squamous cell, melanoma) [56]
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 [57] colorectal, endometrial [57]
mutY homolog (E. coli) MUTYH BER of A paired with 8-oxo-dG [58] colon [58]
TP53 P53 Direct role in HRR, BER, NER and acts in DNA damage response[59] for those pathways and for NHEJ and MMR [60] sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas [61]
NTHL1 NTHL1 BER for Tg, FapyG, 5-hC, 5-hU in dsDNA[62] Colon cancer, endometrial cancer, duodenal cancer, basal-cell carcinoma[63]

See also

References

  1. ↑ "Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation". Int J Mol Sci 17 (11): 1840. 2016. doi:10.3390/ijms17111840. PMID 27827925. 
  2. ↑ "Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss". Cell Stem Cell 1 (1): 113–26. 2007. doi:10.1016/j.stem.2007.03.002. PMID 18371340. 
  3. ↑ "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Rep. 5 (5): 503–9. 2004. doi:10.1038/sj.embor.7400127. PMID 15105825. 
  4. ↑ "The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency". PLOS ONE 9 (4): e93568. 2014. doi:10.1371/journal.pone.0093568. PMID 24740260. Bibcode: 2014PLoSO...993568R. 
  5. ↑ "DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells". Free Radic. Biol. Med. 48 (10): 1435–43. 2010. doi:10.1016/j.freeradbiomed.2010.02.033. PMID 20193758. 
  6. ↑ "XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase". DNA Repair (Amst.) 10 (7): 697–713. 2011. doi:10.1016/j.dnarep.2011.04.028. PMID 21571596. 
  7. ↑ 7.0 7.1 Cite error: Invalid <ref> tag; no text was provided for refs named Gregg
  8. ↑ "Deficiency in the nuclease activity of xeroderma pigmentosum G in mice leads to hypersensitivity to UV irradiation". Mol. Cell. Biol. 24 (6): 2237–42. 2004. doi:10.1128/MCB.24.6.2237-2242.2004. PMID 14993263. 
  9. ↑ "Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability". Mol. Cell 61 (4): 535–46. 2016. doi:10.1016/j.molcel.2015.12.026. PMID 26833090. 
  10. ↑ "Nucleotide excision repair 3' endonuclease XPG stimulates the activity of base excision repair enzyme thymine glycol DNA glycosylase". Nucleic Acids Res. 27 (4): 979–83. 1999. doi:10.1093/nar/27.4.979. PMID 9927729. 
  11. ↑ "Factors influencing the removal of thymine glycol from DNA in γ-irradiated human cells". Factors influencing the removal of thymine glycol from DNA in gamma-irradiated human cells. Progress in Nucleic Acid Research and Molecular Biology. 68. 2001. 139–49. doi:10.1016/S0079-6603(01)68096-6. ISBN 9780125400688. 
  12. ↑ 12.0 12.1 "Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome". J. Mol. Biol. 428 (1): 62–78. 2016. doi:10.1016/j.jmb.2015.11.020. PMID 26616585. 
  13. ↑ 13.0 13.1 13.2 13.3 "The role of CSA and CSB protein in the oxidative stress response". Mech. Ageing Dev. 134 (5–6): 261–9. 2013. doi:10.1016/j.mad.2013.03.006. PMID 23562424. 
  14. ↑ "Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality". PLOS Genet. 9 (4): e1003431. 2013. doi:10.1371/journal.pgen.1003431. PMID 23637614. 
  15. ↑ "Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts". Mol. Cell. Biol. 31 (17): 3630–8. 2011. doi:10.1128/MCB.01462-10. PMID 21730288. 
  16. ↑ 16.0 16.1 "Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs". Mech. Ageing Dev. 128 (11–12): 601–8. 2007. doi:10.1016/j.mad.2007.08.006. PMID 17928034. 
  17. ↑ "DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts". Chromosoma 126 (2): 287–298. 2017. doi:10.1007/s00412-016-0590-9. PMID 27136939. 
  18. ↑ "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Mol. Cell. Biol. 27 (23): 8205–14. 2007. doi:10.1128/MCB.00785-07. PMID 17875923. 
  19. ↑ "Methods to Monitor DNA Repair Defects and Genomic Instability in the Context of a Disrupted Nuclear Lamina". The Nuclear Envelope. Methods in Molecular Biology. 1411. 2016. pp. 419–37. doi:10.1007/978-1-4939-3530-7_26. ISBN 978-1-4939-3528-4. 
  20. ↑ "α-N-methylation of damaged DNA-binding protein 2 (DDB2) and its function in nucleotide excision repair". J. Biol. Chem. 289 (23): 16046–56. 2014. doi:10.1074/jbc.M114.558510. PMID 24753253. 
  21. ↑ "NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging". Mech. Ageing Dev. 146-148: 42–52. 2015. doi:10.1016/j.mad.2015.03.012. PMID 25843235. 
  22. ↑ 22.0 22.1 "Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders". Ageing Res. Rev. 33: 30–35. 2017. doi:10.1016/j.arr.2016.06.002. PMID 27287744. 
  23. ↑ "The multifaceted functions of sirtuins in cancer". Nat. Rev. Cancer 15 (10): 608–24. 2015. doi:10.1038/nrc3985. PMID 26383140. 
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  25. ↑ "SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair". EMBO J. 35 (14): 1488–503. 2016. doi:10.15252/embj.201593499. PMID 27225932. 
  26. ↑ "Roles of Werner syndrome protein in protection of genome integrity". DNA Repair (Amst.) 9 (3): 331–44. 2010. doi:10.1016/j.dnarep.2009.12.011. PMID 20075015. 
  27. ↑ "RecQ helicases and PARP1 team up in maintaining genome integrity". Ageing Res. Rev. 23 (Pt A): 12–28. 2015. doi:10.1016/j.arr.2014.12.006. PMID 25555679. 
  28. ↑ "Genomic instability in laminopathy-based premature aging". Nat. Med. 11 (7): 780–5. 2005. doi:10.1038/nm1266. PMID 15980864. 
  29. ↑ 29.0 29.1 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. http://www.benbest.com/lifeext/Nuclear_DNA_in_Aging.pdf. Retrieved 2009-09-29. 
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  31. ↑ "Activation of human MutS homologs by 8-oxo-guanine DNA damage". J. Biol. Chem. 277 (10): 8260–6. March 2002. doi:10.1074/jbc.M111269200. PMID 11756455. 
  32. ↑ Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009 Oct 8;361(15):1475-85.
  33. ↑ "Defective DNA repair and neurodegenerative disease". Cell 130 (6): 991–1004. September 2007. doi:10.1016/j.cell.2007.08.043. PMID 17889645. 
  34. ↑ 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. https://deepblue.lib.umich.edu/bitstream/2027.42/73065/1/j.1474-9728.2004.00081.x.pdf. 
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  38. ↑ "Minding the gap: the underground functions of BRCA1 and BRCA2 at stalled replication forks". DNA Repair (Amst.) 6 (7): 1018–31. 2007. doi:10.1016/j.dnarep.2007.02.020. PMID 17379580. 
  39. ↑ "Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions". Gynecol. Oncol. 136 (1): 3–7. 2015. doi:10.1016/j.ygyno.2014.09.009. PMID 25238946. 
  40. ↑ 40.0 40.1 "Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways". FASEB J. 25 (11): 3849–60. 2011. doi:10.1096/fj.11-185546. PMID 21778326. 
  41. ↑ "Recombinational DNA repair and human disease". Mutat. Res. 509 (1–2): 49–78. 2002. doi:10.1016/s0027-5107(02)00224-5. PMID 12427531. https://zenodo.org/record/1259665. 
  42. ↑ 42.0 42.1 "Nijmegen breakage syndrome (NBS)". Orphanet J Rare Dis 7: 13. 2012. doi:10.1186/1750-1172-7-13. PMID 22373003. 
  43. ↑ "After double-strand break induction by UV-A, homologous recombination and nonhomologous end joining cooperate at the same DSB if both systems are available". J. Cell Sci. 117 (Pt 21): 4935–45. 2004. doi:10.1242/jcs.01355. PMID 15367581. 
  44. ↑ "Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene". Mol Oncol 2 (4): 296–316. 2008. doi:10.1016/j.molonc.2008.09.007. PMID 19383352. 
  45. ↑ "Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair". Proc. Natl. Acad. Sci. U.S.A. 105 (44): 16906–11. 2008. doi:10.1073/pnas.0809380105. PMID 18971343. Bibcode: 2008PNAS..10516906N. 
  46. ↑ "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". Am. J. Hum. Genet. 21 (2): 196–227. 1969. PMID 5770175. 
  47. ↑ "Deficient DNA repair in the human progeroid disorder, Werner syndrome". Mutat. Res. 577 (1–2): 252–9. 2005. doi:10.1016/j.mrfmmm.2005.03.021. PMID 15916783. https://zenodo.org/record/1259235. 
  48. ↑ "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39. 2010. doi:10.1016/j.semcancer.2010.10.002. PMID 20934517. 
  49. ↑ "Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging". Biogerontology 10 (3): 235–52. 2009. doi:10.1007/s10522-008-9205-z. PMID 19083132. 
  50. ↑ "Two primary osteosarcomas in a patient with Rothmund-Thomson syndrome". Clin. Orthop. Relat. Res. 378 (378): 213–23. 2000. doi:10.1097/00003086-200009000-00032. PMID 10986997. 
  51. ↑ "Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights". Mutat. Res. 668 (1–2): 54–72. 2009. doi:10.1016/j.mrfmmm.2009.02.003. PMID 19622404. 
  52. ↑ "Cancer in Fanconi anemia, 1927-2001". Cancer 97 (2): 425–40. 2003. doi:10.1002/cncr.11046. PMID 12518367. 
  53. ↑ 53.0 53.1 "Xeroderma pigmentosum". Orphanet J Rare Dis 6: 70. 2011. doi:10.1186/1750-1172-6-70. PMID 22044607. 
  54. ↑ 54.0 54.1 "Nucleotide excision repair proteins rapidly accumulate but fail to persist in human XP-E (DDB2 mutant) cells". Photochem. Photobiol. 87 (3): 729–33. 2011. doi:10.1111/j.1751-1097.2011.00909.x. PMID 21388382. 
  55. ↑ 55.0 55.1 "DNA repair diseases: What do they tell us about cancer and aging?". Genet. Mol. Biol. 37 (1 Suppl): 220–33. 2014. doi:10.1590/s1415-47572014000200008. PMID 24764756. 
  56. ↑ 56.0 56.1 "Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations". Hum. Mutat. 35 (1): 117–28. 2014. doi:10.1002/humu.22462. PMID 24130121. 
  57. ↑ 57.0 57.1 "Endometrial cancer and Lynch syndrome: clinical and pathologic considerations". Cancer Control 16 (1): 14–22. 2009. doi:10.1177/107327480901600103. PMID 19078925. 
  58. ↑ 58.0 58.1 "MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA". Front Genet 4: 18. 2013. doi:10.3389/fgene.2013.00018. PMID 23450852. 
  59. ↑ "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. 2008. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632. 
  60. ↑ "The role of p53 in treatment responses of lung cancer". Biochem. Biophys. Res. Commun. 331 (3): 868–80. 2005. doi:10.1016/j.bbrc.2005.03.192. PMID 15865943. 
  61. ↑ "Connecting molecular pathways to hereditary cancer risk syndromes". Am Soc Clin Oncol Educ Book 33: 81–90. 2013. doi:10.1200/EdBook_AM.2013.33.81. PMID 23714463. 
  62. ↑ "Base excision repair". Cold Spring Harb Perspect Biol 5 (4): a012583. 2013. doi:10.1101/cshperspect.a012583. PMID 23545420. 
  63. ↑ "NTHL1 defines novel cancer syndrome". Oncotarget 6 (33): 34069–70. 2015. doi:10.18632/oncotarget.5864. PMID 26431160. 

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