Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment.
Increasing evidence suggests that components of the DNA mismatch repair (MMR) pathway play multifunctional roles beyond the scope of mismatch correction, including the modulation of cellular responses to DNA damage and homologous recombination. The heterocomplex consisting of MutS homologous proteins, hMSH4 and hMSH5, is believed to play essential roles in meiotic DNA repair particularly during the process of meiotic homologous recombination (HR). In order to gain a better understanding of the mechanistic basis underlying the roles of these two human MutS proteins, we have identified G-protein pathway suppressor 2 (GPS2) (i.e., an integral component of a deacetylase complex) as an interacting protein partner specifically for the hMSH4-hMSH5 heterocomplex. The interaction with GPS2 is entirely dependent on the physical association between hMSH4 and hMSH5, as disruption of the interaction between hMSH4 and hMSH5 completely abolishes GPS2 recruitment. Our analysis further indicates that the association with GPS2 is mediated through the interface of hMSH4-hMSH5 complex and the N-terminal region of GPS2. Moreover, these three proteins interact in human cells, and analysis of microarray data suggested a coordinated expression pattern of these genes during the onset of meiosis. Together, the results of our present study suggest that the GPS2-associated deacetylase complex might function in concert with hMSH4-hMSH5 during the process of homologous recombination.
Lee
Tai-Hsien
TH
School of Molecular Biosciences and Center for Reproductive Biology, PO Box 644660, Washington State University, Pullman, WA 99164-4660, USA.
Yi
Wei
W
Griswold
Michael D
MD
Zhu
Fengxue
F
Her
Chengtao
C
D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008540:Meiosis; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; C103316:GPS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C409221:MSH4 protein, human; C118481:MSH5 protein, human; D012097:Repressor Proteins