hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair

Anthony T Vo; Fengxue Zhu; Xiling Wu; Fenghua Yuan; Yin Gao; Liya Gu; Guo-Min Li; Tai-Hsien Lee; Chengtao Her

doi:10.1038/sj.embor.7400392

Back

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair

Journal article

Open access

Peer reviewed

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair

Anthony T Vo, Fengxue Zhu, Xiling Wu, Fenghua Yuan, Yin Gao, Liya Gu, Guo-Min Li, Tai-Hsien Lee and Chengtao Her

EMBO reports, Vol.6(5), pp.438-444

05/2005

DOI: https://doi.org/10.1038/sj.embor.7400392

Handle:

https://hdl.handle.net/2376/109593

PMCID: PMC1299302

PMID: 15864295

Files and links (1)

url

https://doi.org/10.1038/sj.embor.7400392View

Published (Version of record) Open

Abstract

Genomic Instability

MutL Protein Homolog 1

Humans

DNA Repair - physiology

Nuclear Proteins - metabolism

Base Pair Mismatch

DNA Repair - genetics

Mutation, Missense

DNA-Binding Proteins - genetics

Neoplasm Proteins - metabolism

DNA-Binding Proteins - deficiency

DNA-Binding Proteins - metabolism

MRE11 Homologue Protein

Adaptor Proteins, Signal Transducing

Protein Binding

HeLa Cells

Neoplasm Proteins - genetics

Nuclear Proteins - genetics

RNA Interference - physiology

Microsatellite Repeats

Carrier Proteins

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.

Metrics

14 Record Views

Details

Title: hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair
Creators: Anthony T Vo - School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, Washington 99164-4660, USA
Fengxue Zhu
Xiling Wu
Fenghua Yuan
Yin Gao
Liya Gu
Guo-Min Li
Tai-Hsien Lee
Chengtao Her
Publication Details: EMBO reports, Vol.6(5), pp.438-444
Academic Unit: Molecular Biosciences, School of
Publisher: England
Grant note: CA101796 / NCI NIH HHS R01 CA101796 / NCI NIH HHS
Identifiers: 99900547196101842
Language: English
Resource Type: Journal article