DNA错配修复
![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/16/DNA_mismatch_repair.png/220px-DNA_mismatch_repair.png)
DNA错配修复(DNA mismatch repair,簡稱MMR)是生物DNA修復的一種機制,可修補DNA中配對錯誤的鹼基[1][2]。因錯配通常發生在新合成的DNA中(可能為鹼基發生互變異構所致),進行錯配修復時細胞需識別哪一股DNA為新合成者(參見半保留複製),並將其鹼基切除修復,在許多細菌中舊的DNA一般有被甲基化,新合成的DNA則無,故細胞可以此識別新股,其他細菌與真核生物中的識別機制則有所不同,在真核生物中可能是以DNA剛複製後遲滯股(lagging strand)上尚未被連接酶連接的切口(英语:Nick (DNA))識別(且領先股上可能也會有切口)[3]。
大腸桿菌的DNA错配修复過程為MutS(英语:MutS)蛋白二聚體(MutS2)與新合成DNA上配對錯誤的鹼基結合,接著MutL2會與之結合,MutH則切割錯配附近未被甲基化的GATC位點而造成切口,之後MutS2、MutL2與MutH組成的複合體從切口處往錯配處方向移動,過程中UvrD解旋酶可將DNA的兩股分開,並有外切酶可水解新股DNA(包含錯配的鹼基)[註 1],直到經過錯配的鹼基後才停止,最後DNA聚合酶與DNA連接酶可重新合成被移除的DNA序列[4]。真核生物DNA错配修复的過程與原核生物相似,大部分蛋白均與後者的同源,但不同於大腸桿菌的MutS2與MutL2為同源二聚體,真核生物的均為異源二聚體[4],其中MutLα可能具內切酶功能[5]。除上述蛋白外修復過程還有PCNA(英语:PCNA)[6][7]、RPA(英语:Replication protein A)、RFC(英语:Replication factor C)、HMGB1(英语:HMGB1)與DNA聚合酶δ等蛋白參與[4],有依賴外切酶Exo1(英语:Exonuclease 1)的途徑,也有使用其他蛋白切除錯配DNA的途徑[8]。
DNA錯配修復的異常與多種疾病相關,Mut蛋白的突變會造成微衛星不穩定(英语:microsatellite instability),可導致多種癌症,例如遗传性非息肉病性结直肠癌(英语:hereditary nonpolyposis colorectal cancer)(HNPCC)即為MSH2(英语:MSH2)或MLH1(英语:MLH1)等基因突變所致[9],單一基因突變即可致病,兩個Mut蛋白的基因皆突變則可能導致透克氏症(错配修复癌症症候群,CMMR-D),常出現早發的結腸癌或腦癌[10]。除Mut蛋白的DNA序列突變外,啟動子甲基化等表觀遺傳修飾與miR-155(英语:miR-155)過度表現等機制也會因降低這些蛋白的表現而抑制DNA錯配修復,進而導致癌症[11] [12]。
註腳
- ^ 外切酶種類隨MutH切割的相對位置而異,若切割位點在錯配鹼基的5端,則會使用RecJ或ExoVII等由5端至3端水解的外切酶,反之則使用ExoI或ExoX等由3端至5端水解的外切酶[4]。
參見
參考文獻
- ^ Iyer RR, Pluciennik A, Burdett V, Modrich PL. DNA mismatch repair: functions and mechanisms. Chemical Reviews. February 2006, 106 (2): 302–23. PMID 16464007. doi:10.1021/cr0404794.
- ^ Larrea AA, Lujan SA, Kunkel TA. SnapShot: DNA mismatch repair. Cell. May 2010, 141 (4): 730–730.e1. PMID 20478261. doi:10.1016/j.cell.2010.05.002.
- ^ Heller RC, Marians KJ. Replisome assembly and the direct restart of stalled replication forks. Nature Reviews. Molecular Cell Biology. December 2006, 7 (12): 932–43. PMID 17139333. doi:10.1038/nrm2058.
- ^ 4.0 4.1 4.2 4.3 Li GM. Mechanisms and functions of DNA mismatch repair.. Cell Res. 2008, 18 (1): 85–98. PMID 18157157. doi:10.1038/cr.2007.115.
- ^ Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair.. Cell. 2006, 126 (2): 297–308. PMID 16873062. doi:10.1016/j.cell.2006.05.039.
- ^ Pluciennik A, Dzantiev L, Iyer RR, Constantin N, Kadyrov FA, Modrich P. PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair. Proceedings of the National Academy of Sciences of the United States of America. September 2010, 107 (37): 16066–71. PMC 2941292
. PMID 20713735. doi:10.1073/pnas.1010662107.
- ^ Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. July 2006, 126 (2): 297–308. PMID 16873062. doi:10.1016/j.cell.2006.05.039.
- ^ Goellner EM, Putnam CD, Kolodner RD. Exonuclease 1-dependent and independent mismatch repair.. DNA Repair (Amst). 2015, 32: 24–32. PMC 4522362
. PMID 25956862. doi:10.1016/j.dnarep.2015.04.010.
- ^ Ring, Kari L.; Garcia, Christine; Thomas, Martha H.; Modesitt, Susan C. Current and future role of genetic screening in gynecologic malignancies. American Journal of Obstetrics and Gynecology. 2017, 217 (5): 512–521 [2021-05-07]. ISSN 1097-6868. PMID 28411145. doi:10.1016/j.ajog.2017.04.011. (原始内容存档于2021-05-12).
- ^ OMIM 276300
- ^ Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. May 2005, 128 (5): 1160–71. PMID 15887099. doi:10.1053/j.gastro.2005.01.056.
- ^ Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, et al. Modulation of mismatch repair and genomic stability by miR-155. Proceedings of the National Academy of Sciences of the United States of America. April 2010, 107 (15): 6982–7. PMC 2872463
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