Title:MutS Homologues hMSH4 and hMSH5: Genetic Variations, Functions, and Implications in Human Diseases
Volume: 14
Issue: 2
Author(s): Nicole Clark, Xiling Wu and Chengtao Her
Affiliation:
Keywords:
DNA damage response, Double-strand break (DSB), DNA mismatch repair (MMR), Homologous recombination
(HR), MSH4, MSH5, MutS homologues, Single nucleotide polymorphism (SNP)
Abstract: The prominence of the human mismatch repair (MMR) pathway is clearly reflected by the causal link between
MMR gene mutations and the occurrence of Lynch syndrome (or HNPCC). The MMR family of proteins also carries out
a plethora of diverse cellular functions beyond its primary role in MMR and homologous recombination. In fact, members
of the MMR family of proteins are being increasingly recognized as critical mediators between DNA damage repair and
cell survival. Thus, a better functional understanding of MMR proteins will undoubtedly aid the development of strategies
to effectively enhance apoptotic signaling in response to DNA damage induced by anti-cancer therapeutics. Among the
five known human MutS homologs, hMSH4 and hMSH5 form a unique heterocomplex. However, the expression profiles
of the two genes are not correlated in a number of cell types, suggesting that they may function independently as well.
Consistent with this, these two proteins are promiscuous and thought to play distinct roles through interacting with different
binding partners. Here, we describe the gene and protein structures of eukaryotic MSH4 and MSH5 with a particular
emphasis on their human homologues, and we discuss recent findings of the roles of these two genes in DNA damage response
and repair. Finally, we delineate the potential links of single nucleotide polymorphism (SNP) loci of these two
genes with several human diseases.
