DNA mismatch repair and cancer

Abstract

DNA mismatch repair (MMR) is an important genome caretaker system. It ensures genomic stability by correcting mismatches generated during DNA replication and recombination and by triggering apoptosis of cells with large amounts of DNA damage. Protein components responsible for these reactions are highly conserved through evolution, and homologs of bacterial MutS and MutL, which are key players in the initiation steps of both the strand-specific mismatch correction and MMR-dependent apoptotic signaling, have been identified in human cells. Inactivation of genes encoding these activities leads to genome-wide instability, particularly in simple repetitive sequences, and predisposition to certain types of cancer, including hereditary non-polyposis colorectal cancer.

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…Thus, Boland and colleagues restored MMR to an hMLH1 -deficient colorectal tumour cell line by the transfer of chromosome 3 harbouring a wild type copy of hMLH1 (Koi et al, 1994). Similar experiments were carried out for tumour cell lines deficient in MSH6, PMS2, and MLH1 (reviewed in Li, 2003).…”

“…In HNPCC tumours, more than 90% exhibit MSI (Soreide, 2007). Early attempts at identifying the genetic basis for HNPCC revealed frequent insertions and deletions at di-and trinucleotide repeats or microsatellite regions at a putative HNPCC locus on human chromosome 2 as well as throughout the genome (see Li, 2003). These mutations were called replication error positive (RER + ).…”

Gene therapy progress and prospects: targeted gene repair

“…Finally, in many of the gene repair assays, the C/C mismatch is 'repaired' quite efficiently 22,25,44 in contrast to the expected results based on mispair correction hierarchy. 45 This could infer that the replication mode is operational since the C/C mismatch is the least recognized mismatch and in this case, could be tolerated through several rounds of replication. Thus, cells deficient in MMR may enable the gene repair reaction to take place with higher efficiency.…”

Evidence That a Mutation in the MLH1 3′-Untranslated Region Confers a Mutator Phenotype and Mismatch Repair Deficiency in Patients with Relapsed Leukemia

“…Interestingly, despite that all above MSH and MLH genes are implicated in MMR, almost all MMR deficient cancers are associated with alterations in MSH2 and MLH1 (2-4) characterized by either genetic mutations in these genes or hypermethylation of the MLH1 promoter, which epigenetically silences the MLH1 expression (1). The selectively targeting on MSH2 and MLH1 for alterations in HNPCC and other MMR deficient cancers appears to be consistent with the fact MSH2 or MLH1 is an obligating subunit in each of the MutS and MutL heterodimers, whereas the other MSH and MLH components are functionally redundant (5).…”

“…In humans, at least three MSH genes (MSH2, MSH3, and MSH6) and four MLH genes (MLH1, MLH3, PMS1, and PMS2) have been identified. The MSH gene products form the MSH2-MSH6 (also called MutS␣) and MSH2-MSH3 (MutS␤) heterodimers, whereas the MLH gene products constitute heterodimers of MLH1-PMS2 (MutL␣), MLH1-PMS1 (MutL␤), and MLH1-MLH3 (MutL␥) (1). The importance of MMR in maintaining genomic stability is underscored by the fact that defects in this system are the genetic basis of certain types of hereditary and sporadic human cancers, including hereditary non-polyposis colorectal cancer (HNPCC) (1)(2)(3)(4).…”