DNA mismatch repair

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Diagram of DNA mismatch repair pathways. The first column depicts mismatch repair in eukaryotes, while the second depicts repair in most bacteria. The third column shows mismatch repair, to be specific in E. coli.
Micrograph showing loss of staining for MLH1 in colorectal adenocarcinoma in keeping with DNA mismatch repair (left of image) and benign colorectal mucosa (right of image).

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.[1][2]

Mismatch repair is strand-specific. During DNA synthesis the newly synthesised (daughter) strand will commonly include errors. In order to begin repair, the mismatch repair machinery distinguishes the newly synthesised strand from the template (parental). In gram-negative bacteria, transient hemimethylation distinguishes the strands (the parental is methylated and daughter is not). However, in other prokaryotes and eukaryotes, the exact mechanism is not clear. It is suspected that, in eukaryotes, newly synthesized lagging-strand DNA transiently contains nicks (before being sealed by DNA ligase) and provides a signal that directs mismatch proofreading systems to the appropriate strand. This implies that these nicks must be present in the leading strand, and evidence for this has recently been found.[3] Recent work[4] has shown that nicks are sites for RFC-dependent loading of the replication sliding clamp, proliferating cell nuclear antigen (PCNA), in an orientation-specific manner, such that one face of the donut-shape protein is juxtaposed toward the 3'-OH end at the nick. Loaded PCNA then directs the action of the MutLalpha endonuclease [5] to the daughter strand in the presence of a mismatch and MutSalpha or MutSbeta.

Any mutational event that disrupts the superhelical structure of DNA carries with it the potential to compromise the genetic stability of a cell. The fact that the damage detection and repair systems are as complex as the replication machinery itself highlights the importance evolution has attached to DNA fidelity.

Examples of mismatched bases include a G/T or A/C pairing (see DNA repair). Mismatches are commonly due to tautomerization of bases during DNA replication. The damage is repaired by recognition of the deformity caused by the mismatch, determining the template and non-template strand, and excising the wrongly incorporated base and replacing it with the correct nucleotide. The removal process involves more than just the mismatched nucleotide itself. A few or up to thousands of base pairs of the newly synthesized DNA strand can be removed.

  1. ^ Iyer RR, Pluciennik A, Burdett V, Modrich PL (February 2006). "DNA mismatch repair: functions and mechanisms". Chemical Reviews. 106 (2): 302–23. doi:10.1021/cr0404794. PMID 16464007.
  2. ^ Larrea AA, Lujan SA, Kunkel TA (May 2010). "SnapShot: DNA mismatch repair". Cell. 141 (4): 730–730.e1. doi:10.1016/j.cell.2010.05.002. PMID 20478261. S2CID 26969788.
  3. ^ Heller RC, Marians KJ (December 2006). "Replisome assembly and the direct restart of stalled replication forks". Nature Reviews. Molecular Cell Biology. 7 (12): 932–43. doi:10.1038/nrm2058. PMID 17139333. S2CID 27666329.
  4. ^ Pluciennik A, Dzantiev L, Iyer RR, Constantin N, Kadyrov FA, Modrich P (September 2010). "PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair". Proceedings of the National Academy of Sciences of the United States of America. 107 (37): 16066–71. doi:10.1073/pnas.1010662107. PMC 2941292. PMID 20713735.
  5. ^ Kadyrov FA, Dzantiev L, Constantin N, Modrich P (July 2006). "Endonucleolytic function of MutLalpha in human mismatch repair". Cell. 126 (2): 297–308. doi:10.1016/j.cell.2006.05.039. PMID 16873062. S2CID 15643051.