hMRE11 deficiency leads to microsatellite instability and defective DNA mismatch repair.
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.
Vo
Anthony T
AT
School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, Washington 99164-4660, USA.
Zhu
Fengxue
F
Wu
Xiling
X
Yuan
Fenghua
F
Gao
Yin
Y
Gu
Liya
L
Li
Guo-Min
GM
Lee
Tai-Hsien
TH
Her
Chengtao
C
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D000076228:MRE11 Homologue Protein; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C121766:MRE11 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D000070957:MutL Protein Homolog 1