The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations.
Our previous studies indicate that hMRE11 plays a role in MMR, and this function of hMRE11 is most likely mediated by the hMLH1-hMRE11 interaction. Here, we explored the functional implications of the hMLH1-hMRE11 interaction in MMR and the effects of hMLH1 mutations on their interaction. Our in vitro MMR assay demonstrated that the dominant-negative hMRE11(452-634) mutant peptide (i.e., harboring only the hMLH1-interacting domain) imparted a significant reduction in both 3' excision and 3'-directed MMR activities. Furthermore, the expression of hMRE11(452-634), and to a lesser extent hMRE11(1-634) (ATLD1), impaired G2/M checkpoint control in response to MNU and cisplatin treatments, rendering cells resistant to killings by these two anticancer drugs. Analysis of 38 hMLH1 missense mutations showed that the majority of mutations caused significant (>50%) reductions in their interaction with hMRE11, suggesting a potential link between aberrant protein interaction and the pathogenic effects of hMLH1 variants.
Zhao
Nianxi
N
School of Molecular Biosciences and Center for Reproductive Biology, P.O. Box 644660, Washington State University, Pullman, WA 99164-4660, USA.
Zhu
Fengxue
F
Yuan
Fenghua
F
Haick
Anoria K
AK
Fukushige
Shinichi
S
Gu
Liya
L
Her
Chengtao
C
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020137:Base Pair Mismatch; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase / Q000235:genetics; D006801:Humans; D000076228:MRE11 Homologue Protein; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C121766:MRE11 protein, human; D009687:Nuclear Proteins; D010446:Peptide Fragments; D000076228:MRE11 Homologue Protein; D000070957:MutL Protein Homolog 1