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Physical and Functional Interaction between hMSH5 and c-Abl

School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington

Requests for reprints: Chengtao Her, School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, P.O. Box 644660, Pullman, WA 99164-4660. Phone: 509-335-7537; Fax: 509-335-9688; E-mail: cher{at}wsu.edu.

Despite being a member of the mismatch repair family of proteins, the biological functions of hMSH5 in human cells are presently elusive. Here, we report a novel physical and functional interaction between hMSH5 and c-Abl; the latter is a critical non–receptor tyrosine kinase involved in many critical cellular functions including DNA damage response, in which the kinase activity is normally suppressed in the absence of biological challenges. Our data indicate that hMSH5 associates with c-Abl in vivo, which is mediated by a direct physical interaction between the NH₂ terminus (residues 1-109) of hMSH5 and the c-Abl SH3 domain. This physical interaction facilitates the activation of c-Abl tyrosine kinase and the phosphorylation of hMSH5 in response to ionizing radiation. Our data also indicate that the hMSH5 P29S variant overactivates the c-Abl tyrosine kinase activity. Furthermore, it seems that the tyrosine phosphorylation of hMSH5 promotes the dissociation of hMSH4-hMSH5 heterocomplex. Together, the revealed physical and functional interaction of hMSH5 with c-Abl implies that the interplay between hMSH5 and c-Abl could manipulate cellular responses to ionizing radiation–induced DNA damages. (Cancer Res 2006; 66(1): 151-8)

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