Non-canonical actions of mismatch repair

The focus of this article is on the DNA binding and ATPase activities of the mismatch repair (MMR) protein, MutS—our current understanding of how this protein uses ATP to fuel its actions on DNA and initiate repair via interactions with MutL, the next protein in the pathway. Structure-function and kinetic studies have yielded detailed views of the MutS mechanism of action in MMR. How MutS and MutL work together after mismatch recognition to enable strand-specific nicking, which leads to strand excision and synthesis, is less clear and remains an active area of investigation.

Section: Ongoing Research On How Atpase-coupled Actions Of Muts Anmentioning

confidence: 99%

Mismatch binding, ADP–ATP exchange and intramolecular signaling during mismatch repair

Hingorani

2016

“…As discussed in more detail elsewhere in this issue [20], DNA repair of base damages, including mismatched uracils, relies on the MMR and BER pathways [21, 22]. Canonical MMR uses a heterodimer complex formed by either MutSα, consisting of MSH2 and MSH6, or MutSβ, formed by MSH2 and MSH3, to recognize and bind to mismatches.…”

Section: Introduction To Aid and Canonical Dna Repairmentioning

confidence: 99%

Antibody diversification caused by disrupted mismatch repair and promiscuous DNA polymerases

Zanotti

Gearhart

2016

The enzyme activation-induced deaminase (AID) targets the immunoglobulin loci in activated B cells and creates DNA mutations in the antigen-binding variable region and DNA breaks in the switch region through processes known, respectively, as somatic hypermutation and class switch recombination. AID deaminates cytosine to uracil in DNA to create a U:G mismatch. During somatic hypermutation, the MutSα complex binds to the mismatch, and the error-prone DNA polymerase η generates mutations at A and T bases. During class switch recombination, both MutSα and MutLα complexes bind to the mismatch, resulting in double-strand break formation and end-joining. This review is centered on the mechanisms of how the MMR pathway is commandeered by B cells to generate antibody diversity.

“…Studies in model organisms and human cells have demonstrated that the MMR system has multiple functions in DNA metabolism ((1–16), and other reviews in this special issue). Most functions of the MMR system promote genome stability, but some of its functions contribute to the instability of certain genomic loci (7,17,18). Repair of DNA mismatches that are formed during replication and homologous recombination is the major genetic stabilization function of the MMR system (19–25).…”

Section: Introductionmentioning

confidence: 99%

“…The most common substrates for the MMR system are small DNA insertion/deletion loops and single DNA base-base mispairs (27–29). The MMR system also corrects DNA mispairs containing 8-oxoguanine and other oxidatively damaged bases (17,30–33). Furthermore, the MMR system removes 1-nucleotide Okazaki fragment flaps (34) and single ribonucleotides, which are incorporated into DNA opposite noncomplementary deoxyribonucleotides (35).…”

Section: Introductionmentioning

confidence: 99%

Endonuclease activities of MutLα and its homologs in DNA mismatch repair

Kadyrova

Kadyrov

2016

MutLα is a key component of the DNA mismatch repair system in eukaryotes. The DNA mismatch repair system has several genetic stabilization functions. Of these functions, DNA mismatch repair is the major one. The loss of MutLα abolishes DNA mismatch repair, thereby predisposing humans to cancer. MutLα has an endonuclease activity that is required for DNA mismatch repair. The endonuclease activity of MutLα depends on the DQHA(X)2E(X)4E motif which is a part of the active site of the nuclease. This motif is also present in many bacterial MutL and eukaryotic MutLγ proteins, DNA mismatch repair system factors that are homologous to MutLα. Recent studies have shown that yeast MutLγ and several MutL proteins containing the DQHA(X)2E(X)4E motif possess endonuclease activities. Here, we review the endonuclease activities of MutLα and its homologs in the context of DNA mismatch repair.