Postreplicative Mismatch Repair

Jiricny, Josef

doi:10.1101/cshperspect.a012633

Cited by 272 publications

(253 citation statements)

References 178 publications

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“…mutator phenotype | genome instability | DNA replication fidelity | DNA excision | DNA repair D NA mismatch repair (MMR) is a key pathway in DNA metabolism that acts on mispaired bases that occur in replication and recombination intermediates, and as the result of some types of chemical damage to DNA (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). MMR also plays an important role in some types of cellular DNA damage responses (11)(12)(13)(14).…”

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confidence: 99%

Reconstitution of Saccharomyces cerevisiae DNA polymerase ε-dependent mismatch repair with purified proteins

Bowen

Kolodner

2017

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian and Saccharomyces cerevisiae mismatch repair (MMR) proteins catalyze two MMR reactions in vitro. In one, mispair binding by either the MutS homolog 2 (Msh2)-MutS homolog 6 (Msh6) or the Msh2-MutS homolog 3 (Msh3) stimulates 5′ to 3′ excision by exonuclease 1 (Exo1) from a single-strand break 5′ to the mispair, excising the mispair. In the other, Msh2-Msh6 or Msh2-Msh3 activate the MutL homolog 1 (Mlh1)-postmeiotic segregation 1 (Pms1) endonuclease in the presence of a mispair and a nick 3′ to the mispair, to make nicks 5′ to the mispair, allowing Exo1 to excise the mispair. DNA polymerase δ (Pol δ) is thought to catalyze DNA synthesis to fill in the gaps resulting from mispair excision. However, colocalization of the S. cerevisiae mispair recognition proteins with the replicative DNA polymerases during DNA replication has suggested that DNA polymerase e (Pol e) may also play a role in MMR. Here we describe the reconstitution of Pol e-dependent MMR using S. cerevisiae proteins. A mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Δ1N, PCNA, and Pol e was found to catalyze both short-patch and long-patch 5′ nick-directed MMR of a substrate containing a +1 (+T) mispair. When the substrate contained a nick 3′ to the mispair, a mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Δ1N, PCNA, and Pol e was found to catalyze an MMR reaction that required Mlh1-Pms1. These results demonstrate that Pol e can act in eukaryotic MMR in vitro.mutator phenotype | genome instability | DNA replication fidelity | DNA excision | DNA repair

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confidence: 99%

Reconstitution of Saccharomyces cerevisiae DNA polymerase ε-dependent mismatch repair with purified proteins

Bowen

Kolodner

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Our knowledge of the mechanism of eukaryotic MMR comes from several general lines of investigation (3)(4)(5)(6)(7)(8)(9). Studies of bacterial MMR have provided a basic mechanistic framework for comparative studies (5).…”

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confidence: 99%

“…DNA replication fidelity | genome instability | mutator phenotype | cancer | mutagenesis D NA mismatch repair (MMR) is a critical DNA repair pathway that is coupled to DNA replication in eukaryotes where it corrects misincorporation errors made during DNA replication (1)(2)(3)(4)(5)(6)(7)(8)(9). This pathway prevents mutations and acts to prevent the development of cancer (10,11).…”

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confidence: 99%

Reconstitution of long and short patch mismatch repair reactions using Saccharomyces cerevisiae proteins

Bowen¹,

Smith²,

Srivatsan³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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A problem in understanding eukaryotic DNA mismatch repair (MMR) mechanisms is linking insights into MMR mechanisms from genetics and cell-biology studies with those from biochemical studies of MMR proteins and reconstituted MMR reactions. This type of analysis has proven difficult because reconstitution approaches have been most successful for human MMR whereas analysis of MMR in vivo has been most advanced in the yeast Saccharomyces cerevisiae. Here, we describe the reconstitution of MMR reactions using purified S. cerevisiae proteins and mispaircontaining DNA substrates. A mixture of MutS homolog 2 (Msh2)-MutS homolog 6, Exonuclease 1, replication protein A, replication factor C-Δ1N, proliferating cell nuclear antigen and DNA polymerase δ was found to repair substrates containing TG, CC, +1 (+T), +2 (+GC), and +4 (+ACGA) mispairs and either a 5′ or 3′ strand interruption with different efficiencies. The Msh2-MutS homolog 3 mispair recognition protein could substitute for the Msh2-Msh6 mispair recognition protein and showed a different specificity of repair of the different mispairs whereas addition of MutL homolog 1-postmeiotic segregation 1 had no affect on MMR. Repair was catalytic, with as many as 11 substrates repaired per molecule of Exo1. Repair of the substrates containing either a 5′ or 3′ strand interruption occurred by mispair binding-dependent 5′ excision and subsequent resynthesis with excision tracts of up to ∼2.9 kb occurring during the repair of the substrate with a 3′ strand interruption. The availability of this reconstituted MMR reaction now makes possible detailed biochemical studies of the wealth of mutations identified that affect S. cerevisiae MMR.DNA replication fidelity | genome instability | mutator phenotype | cancer | mutagenesis

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“…The newly synthesized strand containing mismatches is targeted for excision followed by highfidelity resynthesis and ligation. Nevertheless, any scheme must reconcile action at a distance (i.e., the mismatch and a strand-specific signal for excision can be far apart) (7)(8)(9). MMR in eukaryotes features two families of MMR proteins, heterodimeric homologs of bacterial MutS (MSH) or MutL (MLH).…”

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confidence: 99%