The Role of MutS Homologues MSH4 and MSH5 in DNA Metabolism and Damage Response

Abstract

The DNA mismatch repair (MMR) pathway is one of the most important genome surveillance systems involved in governing faithful transmission of genetic information during DNA replication and homologous recombination (Jiricny 2006). MMR deficiency attributes to a phenotype known as microsatellite instability (MSI), a condition that predisposes individuals to a heightened risk of cancer development (Harfe & JinksRobertson 2000; Iyer et al. 2006; Jiricny 2006; Kunkel & Erie 2005). Notably, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is the most common malignancy identified in individuals with MMR gene mutations. The MMR pathway relies on the coordinated functions of a family of proteins that recognize mismatched nucleotides and initiate subsequent repair actions ranging from excision of a fragment of DNA containing the mismatched nucleotide to DNA repair synthesis. The MMR system is well conserved evolutionarily from bacteria to humans, of which the eukaryotic MMR pathway is evolved to possess multiple homologous genes that carry out conserved and diverse functions corresponding to their bacterial counterparts (Modrich 1991). Genes encoding homologues of the bacterial MMR proteins such as MutS and MutL have been identified in a variety of eukaryotes including yeast, plants, nematodes, and mammals. However, the bacterial MutH appears to be an exception—this methylation-sensitive endonuclease, exclusively functioning in gram-negative bacteria, directs the action of MMR to hemimethylated newly synthesized bacterial DNA (Iyer et al. 2006). All eukaryotic organisms possess multiple MutS homologues—collectively known as MSH proteins—which may number as high as seven (MSH1 to MSH7), although the mitochondrial-localizing MSH1 of Saccharomyces cerevisiae (Reenan & Kolodner 1992) and the Arabadopsis thalia MSH7 (Culligan & Hays 1997) do not appear to be fully conserved (Fishel & Wilson 1997). The functionality of these proteins is similar to that of their counterparts in bacteria such as Eschericia coli. Prokaryotic MutS exists as a homodimer, while eukaryotic MSH proteins form heterodimers in the forms of MSH2-MSH3, MSH2MSH6 and MSH4-MSH5. Two of these eukaryotic heterodimers (MSH2-MSH3 and MSH2-