MLH 1 Mutation Links BACH 1 / FANCJ to Colon Cancer , Pr R aling , and Insight toward Directed

wnloaded ects in MLH1, as with other mismatch repair (MMR) proteins, are the primary cause of hereditary lyposis colon cancer (HNPCC). Mutations in MMR genes often disrupt mismatch repair and MMR ing functions. However, some HNPCC-associated mutations have unknown pathogenicity. Here, cover an MLH1 clinical mutation with a leucine (L)-to-histidine (H) amino acid change at position at ablates MLH1 binding to FANCJ. Given that a DNA helicase is not essential for mammalian in vitro, we considered that loss of MLH1 binding to FANCJ could alter MMR signaling. Consistent his hypothesis, FANCJ-deficient cells exhibit delayed MMR signaling and apoptotic responses enerate resistance to agents that induce O-methylguanine lesions. Our data indicate that the delay R signaling provides time for the methylguanine methyltransferase (MGMT) enzyme to reverse methylation. In essence, FANCJ deficiency alters the competition between two pathways: MGMTrvival versus MMR-prodeath. This outcome could explain the HNPCC familial cancers that present crosatellite stable and with intact MMR, such as MLH. Importantly, the link between FANCJ as mi and HNPCC provides insight toward directed therapies because loss of the FANCJ/MLH1 interaction also uniquely sensitizes cells to DNA cross-linking agents. Cancer Prev Res; 3(11); 1409–16. ©2010 AACR.