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

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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 non-polyposis 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.

Original languageEnglish (US)
Pages (from-to)438-444
Number of pages7
JournalEMBO Reports
Volume6
Issue number5
DOIs
StatePublished - May 1 2005

Fingerprint

Microsatellite Instability
DNA Mismatch Repair
Microsatellite Repeats
Colorectal Neoplasms
Repair
DNA
Mutation
Missense Mutation
RNA Interference
HeLa Cells
Tumors
RNA
Defects
Proteins

Keywords

  • DNA mismatch repair
  • hMLH1
  • hMRE11
  • HNPCC
  • Microsatellite instability

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair. / Vo, Anthony T.; Zhu, Fengxue; Wu, Xiling; Yuan, Fenghua; Gao, Yin; Gu, Liya; Li, Guo Min; Lee, Tai Hsien; Her, Chengtao.

In: EMBO Reports, Vol. 6, No. 5, 01.05.2005, p. 438-444.

Research output: Contribution to journalArticle

Vo, Anthony T. ; Zhu, Fengxue ; Wu, Xiling ; Yuan, Fenghua ; Gao, Yin ; Gu, Liya ; Li, Guo Min ; Lee, Tai Hsien ; Her, Chengtao. / hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair. In: EMBO Reports. 2005 ; Vol. 6, No. 5. pp. 438-444.
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