i. In eukaryotes, the best characterized system is S. cerevisiae; human components have been identified and assayed in cell extracts and reconstituted systems. E. coli MMR is initiated by recognition of mismatched bases by MutS; MutL relays MutS activity to downstream events. Msh proteins are the mammalian counterparts of MutS; Mlh and Pms proteins are the counterparts of MutL. Base excision is mediated by Exo1; protection of ssDNA and prevention of hairpin formation is provided by Rpa - a trimeric single-stranded DNA-binding protein complex. Repair of the single-stranded gap involves re-synthesis and ligation carried out by DNA polymerase delta and DNA ligase 1. Several polymerases maintain the integrity of the genome by carrying out DNA replication, recombination and repair. Delta and epsilon polymerases are involved in DNA replication and in DNA base and strand repair pathways; only delta appears to be specifically involved in MMR. Base excision and nucleotide excision are base repair pathways that fix DNA damaged by exogenous or endogenous agents. Polymerase delta requires a moving platform; this is provided by the processivity factor Pcna (known as the clamp) and a pentameric protein complex Rfc (Replication factor C) that loads it (known as the clamp-loader). Rfc binds the ring shaped Pcna in the presence of ATP; ATP-bound Rfc binds DNA and this event prompts ATP hydrolysis and ejection of the Rfc complex. The now closed Pcna clamp on DNA is in the proper orientation for use by the polymerase. Delta polymerase and Rcf appear to bind/compete for the same site on the Pcna clamp. Interactions between components of MMR and between some of these components and other proteins have been established; the significance of many remains elusive. And so are many of the molecular details of the pathway such as strand specificity and recognition or Rpa clearance amongst them. Alterations in MMR pathway have been implicated in colorectal and other forms of cancer. To see the ontology report for annotations, GViewer and download, click here

[click to see the ontology report for associated GO term - GO:0006298 and KEGG map - map03430]...(less)