Репарация ошибочно спаренных нуклеотидов: различия между версиями

Eukaryotes have <u>M</u>ut<u>L</u> <u>h</u>omologs designated Mlh1 and Pms1. They form a heterodimer which mimics MutL in ''E. coli''. The human homologue of prokaryotic MutL has three forms designated as MutLα, MutLβ and MutLγ. The MutLα complex is made of two subunits MLH1 and PMS2, the MutLβ heterodimer is made of MLH1 and PMS1, while MutLγ is made of MLH1 and MLH3. MutLα acts as the matchmaker or facilitator, coordinating events in mismatch repair. It has recently been shown to be a DNA endonuclease that introduces strand breaks in DNA upon activation by mismatch and other required proteins, MutSa and PCNA. These strand interruptions serve as entry points for an exonuclease activity that removes mismatched DNA. Roles played by MutLβ and MutLγ in mismatch repair are less well understood.

 

MutH has no eukaryotic homolog. Its endonuclease function is taken up by MutL homologs, which have some specialized 5'-3' exonuclease activity. The strand bias for removing mismatches from the newly synthesized daughter strand in eukaryotes may be provided by the free 3’ ends of Okazaki fragments in the new strand created during replication.

 

[[PCNA]] and the β-sliding clamp associate with MutSα/β and MutS, respectively. Although initial reports suggested that the PCNA-MutSα complex may enhance mismatch recognition,<ref>{{cite journal |author=Flores-Rozas H, Clark D, Kolodner RD |title=Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex |journal=Nature Genetics |volume=26 |issue=3 |pages=375–8 |year=2000 |pmid=11062484 |doi=10.1038/81708}}</ref> it has been recently demonstrated<ref>{{cite journal |author=Iyer RR, Pohlhaus TJ, Chen S, Hura GL, Dzantiev L, Beese LS, Modrich P |title=The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair |journal=Journal of Biological Chemistry |volume=283 |issue=19 |pages=13310–9 |year=2008 |pmid=18326858 |doi=10.1074/jbc.M800606200 |pmc=2423938}}</ref> that there is no apparent change in affinity of MutSα for a mismatch in the presence or absence of PCNA. Furthermore, mutants of MutSα that are unable to interact with PCNA [[In vitro|''in vitro'']] exhibit the capacity to carry out mismatch recognition and mismatch excision to near wild type levels. Curiously, such mutants are defective in the repair reaction directed by a 5' strand break, suggesting for the first time MutSα function in a post-excision step of the reaction.

 

Mutations in the human homologues of the Mut proteins affect genomic stability, which can result in [[microsatellite instability]] (MI). MI is implicated in most human cancers. Specifically the overwhelming majority of hereditary nonpolyposis colorectal cancers ([[HNPCC]]) are attributed to mutations in the genes encoding the MutS and MutL homologues [[MSH2]] and [[MLH1]] respectively, which allows them to be classified as tumour suppressor genes.

A subtype of HNPCC is known as [[Muir-Torre Syndrome]] (MTS) which is associated with skin tumors.

 

== См. также ==

 

== Ссылки ==

* ''Sung-Hoon Jun, Tae Gyun Kim, Changill Ban'' [http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2006.05190.x/pdf DNA mismatch repair system. Classical and fresh roles]. FEBS Journal 273 (2006) 1609–1619, doi:10.1111/j.1742-4658.2006.05190.x.

* {{MeshName|DNA+Mismatch+Repair}}

* [http://humbio.ru/humbio/reparation/x0003875.htm Репарация ошибочно спаренных нуклеотидов (mismatch repair)] на сайте «Биология человека».

* [http://humbio.ru/humbio/reparation/x0003875.htm MutL белок] на сайте «Биология человека».

* [http://www.cnshb.ru/AKDiL/0048/base/RR/200001.shtm Репарация] на сайте «Химическая энциклопедия».

* ''Hsieh, P.'' Molecular mechanisms of DNA mismatch repair. Mutat. Res. 486, 71–87 (2001).

 

[[Категория:Репарация ДНК]]