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hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair
Author(s) -
Vo Anthony T,
Zhu Fengxue,
Wu Xiling,
Yuan Fenghua,
Gao Yin,
Gu Liya,
Li GuoMin,
Lee TaiHsien,
Her Chengtao
Publication year - 2005
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400392
Subject(s) - dna mismatch repair , microsatellite instability , biology , genetics , dna repair , missense mutation , mutation , dna , genome instability , cancer research , microsatellite , dna damage , gene , allele
DNA mismatch repair (MMR) is essential in the surveillance of accurate transmission of genetic information, and defects in this pathway lead to microsatellite instability and hereditary nonpolyposis colorectal cancer (HNPCC). Our previous study raised the possibility that hMRE11 might be involved in MMR through physical interaction with hMLH1. Here, we show that hMRE11 deficiency leads to significant increase in MSI for both mono‐ and dinucleotide sequences. Furthermore, RNA‐interference‐mediated hMRE11‐knockdown in HeLa cells results in MMR deficiency. Analysis of seven HNPCC‐associated hMLH1 missense mutations located within the hMRE11‐interacting domain shows that four mutations (L574P, K618T, R659P and A681T) cause near‐complete disruption of the interaction between hMRE11 and hMLH1, and two mutations (Q542L and L582V) cause a 30% reduction of protein interaction. These findings indicate that hMRE11 represents a functional component of the MMR pathway and the disruption of hMLH1–hMRE11 interaction could be an alternative molecular explanation for hMLH1 mutations in a subset of HNPCC tumours.