Repair of DNA mismatches, and of small insertions and deletions, is a fundamental element of genome stability. In humans, these processes are accomplished by various combinations of two classes of factors, MSH (homologs of bacterial MutS) and MLH (homologs of bacterial MutL), some of which are known as PMS, because certain yeast proteins of this class were originally identified as modifiers of post-meiotic segregation. Mutations in some, but not all, of these factors are strongly correlated with hereditary non-polyposis colon cancer (HNPCC) and can cause a variety of defects in DNA repair, which can be confined to either mismatch repair, the repair of small insertions and deletions, or both. Deficiencies in the latter process are manifested as microsatellite instability (MSI), a marker for early-onset HNPCC.

In the January issue of Nature Genetics, Lipkin et al. have reported the identification of another repair factor, MLH3, that interacts with the previously characterized MLH1. Like many of its relatives, MLH3 is closely related to a known yeast protein, Mlh3p. Expression of a mutated dominant negative form of MLH3 induces MSI in cell lines, making it a strong candidate for cancer susceptibility. Moreover, the mouse homolog, Mlh3, maps to the complex trait locus Ccs1, which may be involved in susceptibility to colon cancer and produces an MSI phenotype. Additionally, in situ hybridization data (see picture) indicates that Mlh3 is expressed on epithelial cells of the colon.

But do mutations in MLH3 underlie human colon cancer susceptibility? A paper published by Weber et al . in Cytogenetics and Cell Genetics 86, 142 –147 (1999) reports loss of heterozygosity in the region of chromosome 14q containing MLH3 in approximately 30% of human colorectal cancers. Lipkin's group is also investigating whether specific mutations in MLH3 are associated with susceptibility to colon and other types of human cancers.