Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex

@article{FloresRozas2000ProliferatingCN,
  title={Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex},
  author={Hernan Flores-Rozas and Delbert Clark and Richard David Kolodner},
  journal={Nature Genetics},
  year={2000},
  volume={26},
  pages={375-378}
}
Proliferating cell nuclear antigen (PCNA) is required for mismatch repair (MMR) and has been shown to interact with complexes containing Msh2p or MLH1 (refs 1–4). PCNA has been implicated to act in MMR before and during the DNA synthesis step, although the biochemical basis for the role of PCNA early in MMR is unclear. Here we observe an interaction between PCNA and Msh2p-Msh6p mediated by a specific PCNA-binding site present in Msh6p. An msh6 mutation that eliminated the PCNA-binding site… 
Transfer of the MSH2·MSH6 Complex from Proliferating Cell Nuclear Antigen to Mispaired Bases in DNA*
TLDR
It is shown that PCNA and MSH2·MSH6 form a stable ternary complex with a homoduplex (G/C) DNA, but the addition of ATP or adenosine 5′-O-(thiotriphosphate) restores MSH 2· MSH6 binding to PCNA, presumably by disrupting MSH1·MSh4 binding to the heterod uplex (T/T) DNA.
PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair.
TLDR
Results reveal a central role for PCNA in the Exo1-independent MMR pathway and suggest that Msh2-Msh6 localizes PCNA to repair sites after mispair recognition to activate the Mlh1-Pms1 endonuclease for initiating Exo 1-dependent repair or for driving progressive excision in Exo2-independent repair.
Dominant Saccharomyces cerevisiae msh6 Mutations Cause Increased Mispair Binding and Decreased Dissociation from Mispairs by Msh2-Msh6 in the Presence of ATP*
TLDR
The results indicate that the dominant msh6 mutations cause more stable binding to mispairs and suggest that there may be differences in how base base and insertion misPairs are recognized.
MSH-MLH complexes formed at a DNA mismatch are disrupted by the PCNA sliding clamp.
TLDR
The replication processivity factor proliferating cell nuclear antigen (PCNA), which plays a critical role in MMR at step(s) prior to DNA resynthesis, disrupted preformed ternary complexes, suggesting that PCNA interacts with an MSH-MLH complex formed on DNA mispairs.
Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
TLDR
This review will focus on molecular mechanisms associated with mismatch binding, as well as emerging evidence that MutSα, and in particular, MSH6, is a key protein in MMR-dependent DNA damage response and communication with other DNA repair pathways within the cell.
Effective mismatch repair depends on timely control of PCNA retention on DNA by the Elg1 complex
TLDR
It is shown that timely removal of PCNA from DNA by the Elg1 complex is important to prevent mutations, and suggests that PCNA retention controlled by theElg1complex is critical for efficient MMR.
Multiple factors insulate Msh2-Msh6 mismatch repair activity from defects in Msh2 domain I.
TLDR
Evidence is provided that, in vivo, multiple factors insulate MMR from defects in domain I of Msh2 and insights are provided into how mutations in Msh 2 domain I may cause hereditary non-polyposis colorectal cancer.
Analysis of interactions between mismatch repair initiation factors and the replication processivity factor PCNA.
TLDR
This work utilizes both genetic and surface plasmon resonance techniques to characterize the MLH1-PMS1-PCNA interaction and favors a model in which PCNA acts as a scaffold for consecutive protein-protein interactions that allow for the coordination of MMR steps.
Visualization of Eukaryotic DNA Mismatch Repair Reveals Distinct Recognition and Repair Intermediates
TLDR
The presence of replication machinery-coupled and -independent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric Mlh1-Pms1 foci that represent sites of active MMR, is suggested.
The N terminus of Saccharomyces cerevisiae Msh6 is an unstructured tether to PCNA.
TLDR
It is demonstrated genetically that the NTR of Msh6 has an important role in MMR that is partially redundant with PCNA binding and that flexible linkers are a common theme for PCNA-interacting proteins that may serve to localize these binding partners without tightly restraining them to the immediate vicinity of PCNA.
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TLDR
A point mutation, pol30-104, is identified in the Saccharomyces cerevisiae POL30 gene encoding PCNA that increases the rate of instability of simple repetitive DNA sequences and raises the rates of spontaneous forward mutation.
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TLDR
Eukaryotic mismatch repair (MMR) has been shown to require two different heterodimeric complexes of MutS-related proteins: MSH 2-MSH3 and MSH2- MSH6, and alternative models have been proposed for how these MSH complexes function in MMR.
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TLDR
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TLDR
It is suggested that the repair of a base pair mismatch by the Msh2p-Msh6p-DNA mismatch complex is dependent on the ability of the MSh2p -Msh 6p- DNA mismatch complex to use ATP hydrolysis to activate downstream events in mismatch repair.
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TLDR
The data suggest a PCNA requirement in mismatch repair at a step preceding DNA resynthesis in yeast and human expression libraries, and the ability of PCNA to bind to MLH1 and MSH2 may reflect linkage between mismatch repair and replication.
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TLDR
It is shown that human MSH2, MLH1, PMS2 and proliferating cell nuclear antigen (PCNA) can be co-immunoprecipitated, suggesting formation of a repair initiation complex among these proteins, and that PCNA is required in human mismatch repair not only at the step of repair initiation, but also at theStep of repair DNA re-synthesis.
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TLDR
It is proposed that the MSH2 helix-turn-helix domain mediates changes in Msh2p-Msh6p interactions that are induced by ATP hydrolysis; the net result of these changes is a modulation of mismatch recognition.
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TLDR
The results indicate that S. cerevisiae has two pathways of MSH 2-dependent mismatch repair: one that recognized single-base mispairs and requires MSH2 and MSH6, and a second that recognizes insertion/deletion mispaired and requires a combination of either MSH1-6 or MSh2 andMSH6.
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TLDR
Differential effects of ATP on the stability of MSH2-MSH6-mispair complexes suggested that base-base mispairs and the smaller IDL mis pairs were recognized by a different binding mode than larger IDLMispair recognition was influenced by sequence context, consistent with genetic experiments indicating that MSH 2- MSH6 functions primarily in the repair of base- base and small IDLmispairs.
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TLDR
The results show that PCNA plays an essential role in both DNA replication and DNA repair in vivo.
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