Thus, although the role of haploinsufciency of EXO in colon cancer cannot be ruled out, more evidence has to be gathered before EXO is labeled as an HNPCC gene.It is likely, however, that we have not yet identied all the proteins that participate in MMR.Should some of these be dedicated to MMR only, rather than being involved also in other, vital DNA metabolic processes, mutations in the genes encoding these novel proteins might be found in the HNPCC families that present with MSI <a href="https://www.ncbi.nlm.nih.gov/pubmed/17362206">Targetmol's
3PO</a> tumors but do not carry mutated hMSH, hMLH or hMSH genes.Tumors linked with germline mutations in MMR genes account for around of all colon cancers.However, immunohistochemical screening of unselected colon tumors revealed that up to fail to stain for MMR proteins.Baylin and colleagues were the rst to show that the MMR defect in most of these tumors was linked to the silencing of the hMLH promoter by cytosine methylation. The tantalizing possibility that this gene might be imprinted by cytosine methylation, and that this phenomenon might segregate in HNPCC families like MMR mutations, cannot be ignored, following the identication of an HNPCC patient with one methylated hMLH allele in DNA isolated from blood and a loss of heterozygosity of the wildtype allele in the tumor. Such cases are probably extremely rare, however, certainly when compared to the frequency of hypermethylation of the hMLH promoter in sporadic colon tumors.Many genes tend to be indiscriminately silenced by this process, but if only some are lost, and if these are involved in functions such as growth control and checkpoint control, then this will provide the tumor cells with the selective advantage that will help them to grow out. However, although this mechanism might be at work here, an alternative scenario might also be operating.This phenotype has been ascribed to their failure to arrest at the GM checkpoint following DNA damage.Interestingly, recent studies show that checkpoint activation requires greater quantities of MMR proteins than are needed for mismatch correction. In the colon, the epithelial cells lining the crypts follow a strict program of division, cell migrationdifferentiation and anoikis, which results in the turnover of the crypt cell population every ve days or so.Cells with defective signaling and apoptosis would be expected to default on this program and might grow out into adenomas.The MMR system appears to be involved in activating the GM cellcycle checkpoint following treatment of cells with methylating agents. It should be pointed out that the concentration of MNNG used in this study was very high, such that it could have caused doublestrand breaks in DNA, which are known to activate ATM.It is not clear why doublestrand breaks should signal via MMR.This latter phenomenon, reported to involve the ATM and CHK kinases, might at rst sight appear rather curious, as MMR status has no or only a very minor effect on the sensitivity of cells to IR treatment, particularly when compared to the fold difference in sensitivity to methylating agents.This modication appears to be largely responsible for the cytotoxicity of methylating agents, as cells expressing high amounts of MGMT are resistant to killing by agents such as MNU, MNNG and temozolomide, whereas cells lacking this activity are highly sensitive to these drugs.