WordNet

bring disorder to (同)disarray
a physical condition in which there is a disturbance of normal functioning; "the doctor prescribed some medicine for the disorder"; "everyone gets stomach upsets from time to time" (同)upset
a disturbance of the peace or of public order
move, travel, or proceed toward some place; "He repaired to his cabin in the woods" (同)resort
restore by replacing a part or putting together what is torn or broken; "She repaired her TV set"; "Repair my shoes please" (同)mend, fix, bushel, doctor, furbish up, restore, touch_on
a formal way of referring to the condition of something; "the building was in good repair"
the act of putting something in working order again (同)fix, fixing, fixture, mend, mending, reparation
the 4th letter of the Roman alphabet (同)d

PrepTutorEJDIC

〈U〉『無秩序』,混乱,乱雑(confusion) / 《しばしば複数形で》(社会的・政治的な)粉争,騒動 / 〈C〉(肉体的・精神的な)不調,異常,障害 / …‘の'秩序を乱す / 〈心身〉‘に'異常を起こさせる
…‘を'『修繕する』,修理する / …‘を'『償う』;…‘を'訂正する』 / …‘を'回復する / 修繕(修理)できる / 『修繕』,『修理』,修繕作業 / 〈U〉手入れ(修理)の状態
(大挙して)(…へ)行く(GO)《+『to』+『名』》
〈U〉〈C〉(…の)(量・額などの)不足,欠乏《+『of』(『in』)+『名』》 / 〈C〉不足分,不足量,不足額 / 〈C〉(精神・肉体などの)欠陥
deuteriumの化学記号
deoxyribonucleic acidディオキシリボ核酸

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/11 15:06:35」(JST)

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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.

Examples

Some of the examples include:

Ataxia telangiectasia^[1]
Bloom syndrome
Cockayne's syndrome
Fanconi's anaemia
Progeria (Hutchinson-Gilford Progeria syndrome)^[2]^[3]
Rothmund-Thomson syndrome^[4]^[5]
Trichothiodystrophy^[6]
Werner syndrome
Xeroderma pigmentosum

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] 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]

References

^ Biton S, Dar I, Mittelman L, Pereg Y, Barzilai A, Shiloh Y (June 2006). "Nuclear ataxia-telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells". J. Biol. Chem. 281 (25): 17482–91. doi:10.1074/jbc.M601895200. PMID 16627474.
^ Manju K, Muralikrishna B, Parnaik VK (July 2006). "Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci". J. Cell. Sci. 119 (Pt 13): 2704–14. doi:10.1242/jcs.03009. PMID 16772334.
^ Scaffidi P, Misteli T (May 2006). "Lamin A-dependent nuclear defects in human aging". Science 312 (5776): 1059–63. doi:10.1126/science.1127168. PMC 1855250. PMID 16645051.
^ Brosh RM, Bohr VA (2007). "Human premature aging, DNA repair and RecQ helicases". Nucleic Acids Res. 35 (22): 7527–44. doi:10.1093/nar/gkm1008. PMC 2190726. PMID 18006573.
^ Kitao S, Shimamoto A, Goto M, et al. (May 1999). "Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome". Nat. Genet. 22 (1): 82–4. doi:10.1038/8788. PMID 10319867.
^ Kleijer WJ, Laugel V, Berneburg M, et al. (May 2008). "Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy". DNA Repair (Amst.) 7 (5): 744–50. doi:10.1016/j.dnarep.2008.01.014. PMID 18329345.
^ ^a ^b Best,BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328.
^ Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J (February 2003). "Aging and genome maintenance: lessons from the mouse?". Science 299 (5611): 1355–9. doi:10.1126/science.1079161. PMID 12610296.
^ Mazurek A, Berardini M, Fishel R (March 2002). "Activation of human MutS homologs by 8-oxo-guanine DNA damage". J. Biol. Chem. 277 (10): 8260–6. doi:10.1074/jbc.M111269200. PMID 11756455.
^ Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009 Oct 8;361(15):1475-85.
^ Rass U, Ahel I, West SC (September 2007). "Defective DNA repair and neurodegenerative disease". Cell 130 (6): 991–1004. doi:10.1016/j.cell.2007.08.043. PMID 17889645.
^ 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.
^ Hasty P, Vijg J (April 2004). "Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity". Aging Cell 3 (2): 55–65. doi:10.1111/j.1474-9728.2004.00082.x. PMID 15038819.
^ Hasty P, Vijg J (April 2004). "Rebuttal to Miller: 'Accelerated aging': a primrose path to insight?'". Aging Cell 3 (2): 67–9. doi:10.1111/j.1474-9728.2004.00087.x. PMID 15038820.
^ Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002 Jun;511(2):145-78. Review.
^ Nagaraju G, Scully R (2007). "Minding the gap: the underground functions of BRCA1 and BRCA2 at stalled replication forks". DNA Repair (Amst.) 6 (7): 1018–31. doi:10.1016/j.dnarep.2007.02.020. PMC 2989184. PMID 17379580.
^ Lancaster JM, Powell CB, Chen LM, Richardson DL (2015). "Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions". Gynecol. Oncol. 136 (1): 3–7. doi:10.1016/j.ygyno.2014.09.009. PMID 25238946.
^ ^a ^b Keimling M, Volcic M, Csernok A, Wieland B, Dörk T, Wiesmüller L (2011). "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. doi:10.1096/fj.11-185546. PMID 21778326.
^ Thompson LH, Schild D (2002). "Recombinational DNA repair and human disease". Mutat. Res. 509 (1-2): 49–78. doi:10.1016/s0027-5107(02)00224-5. PMID 12427531.
^ ^a ^b Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M (2012). "Nijmegen breakage syndrome (NBS)". Orphanet J Rare Dis 7: 13. doi:10.1186/1750-1172-7-13. PMC 3314554. PMID 22373003.
^ Rapp A, Greulich KO (2004). "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. doi:10.1242/jcs.01355. PMID 15367581.
^ Bartkova J, Tommiska J, Oplustilova L, Aaltonen K, Tamminen A, Heikkinen T, Mistrik M, Aittomäki K, Blomqvist C, Heikkilä P, Lukas J, Nevanlinna H, Bartek J (2008). "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. doi:10.1016/j.molonc.2008.09.007. PMID 19383352.
^ Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC (2008). "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. doi:10.1073/pnas.0809380105. PMC 2579351. PMID 18971343.
^ German J (1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". Am. J. Hum. Genet. 21 (2): 196–227. PMC 1706430. PMID 5770175.
^ Bohr VA (2005). "Deficient DNA repair in the human progeroid disorder, Werner syndrome". Mutat. Res. 577 (1-2): 252–9. doi:10.1016/j.mrfmmm.2005.03.021. PMID 15916783.
^ Monnat RJ (2010). "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39. doi:10.1016/j.semcancer.2010.10.002. PMC 3040982. PMID 20934517.
^ Singh DK, Ahn B, Bohr VA (2009). "Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging". Biogerontology 10 (3): 235–52. doi:10.1007/s10522-008-9205-z. PMC 2713741. PMID 19083132.
^ Anbari KK, Ierardi-Curto LA, Silber JS, Asada N, Spinner N, Zackai EH, Belasco J, Morrissette JD, Dormans JP (2000). "Two primary osteosarcomas in a patient with Rothmund-Thomson syndrome". Clin. Orthop. Relat. Res. 378: 213–23. doi:10.1097/00003086-200009000-00032. PMID 10986997.
^ Thompson LH, Hinz JM (2009). "Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights". Mutat. Res. 668 (1-2): 54–72. doi:10.1016/j.mrfmmm.2009.02.003. PMC 2714807. PMID 19622404.
^ Alter BP (2003). "Cancer in Fanconi anemia, 1927-2001". Cancer 97 (2): 425–40. doi:10.1002/cncr.11046. PMID 12518367.
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^ ^a ^b Oh KS, Imoto K, Emmert S, Tamura D, DiGiovanna JJ, Kraemer KH (2011). "Nucleotide excision repair proteins rapidly accumulate but fail to persist in human XP-E (DDB2 mutant) cells". Photochem. Photobiol. 87 (3): 729–33. doi:10.1111/j.1751-1097.2011.00909.x. PMC 3082610. PMID 21388382.
^ ^a ^b Menck CF, Munford V (2014). "DNA repair diseases: What do they tell us about cancer and aging?". Genet. Mol. Biol. 37 (1 Suppl): 220–33. doi:10.1590/s1415-47572014000200008. PMC 3983582. PMID 24764756.
^ ^a ^b Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert C, Kannouche P, Soufir N, Sarasin A (2014). "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. doi:10.1002/humu.22462. PMID 24130121.
^ ^a ^b Meyer LA, Broaddus RR, Lu KH (2009). Library/Main Nav/Research and Clinical Trials/Cancer Control Journal/v16n1/14.pdf "Endometrial cancer and Lynch syndrome: clinical and pathologic considerations" Check |url= value (help) (PDF). Cancer Control 16 (1): 14–22. PMC 3693757. PMID 19078925.
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External links

BRCA - Companion Reviews and Search Terms
BRCA1 - Companion Reviews and Search Terms
BRCA2 - Companion Reviews and Search Terms
ATM - Companion Reviews and Search Terms
NBS1 - Companion Reviews and Search Terms
Bloom s syndrome - Companion Reviews and Search Terms
Fanconi s anemia - Companion Reviews and Search Terms
WRN - Companion Reviews and Search Terms
RECQ- Companion Reviews and Search Terms
RECQL4 - Companion Reviews and Search Terms
FANCJ - Companion Reviews and Search Terms
FANCM - Companion Reviews and Search Terms
FANCN - Companion Reviews and Search Terms
XPB - Companion Reviews and Search Terms
XPD - Companion Reviews and Search Terms
XPG - Companion Reviews and Search Terms
MSH6 - Companion Reviews and Search Terms
MUTYH - Companion Reviews and Search Terms
DNA repair and toxicology - Companion Reviews and Search Terms
Neoplasia inherited - Companion Reviews and Search Terms
Neoplasia carcinogenesis - Companion Reviews and Search Terms
Segmental Progeria

UpToDate Contents

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1. リンチ症候群（遺伝性非ポリポーシス大腸癌）の臨床的特徴および診断 clinical features and diagnosis of lynch syndrome hereditary nonpolyposis colorectal cancer
2. リ・フラウメニ症候群 li fraumeni syndrome
3. リンチ症候群（遺伝性非ポリポーシス性大腸癌）：患者および家族のスクリーニング
およびマネージメント lynch syndrome hereditary nonpolyposis colorectal cancer screening and management of patients and families
4. 大腸癌の病理および予後決定因子 pathology and prognostic determinants of colorectal cancer
5. 家族性腺腫性ポリポーシスの臨床症状および診断 clinical manifestations and diagnosis of familial adenomatous polyposis

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