Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research..
The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2-Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5' ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2-Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2-Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2-Msh3 can disrupt DNA replication and repair and highlights the role of Msh2-Msh3 protein abundance in Msh2-Msh3-mediated genomic instability.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
Nucleic acids research - 51(2023), 22 vom: 11. Dez., Seite 12185-12206 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Medina-Rivera, Melisa [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.12.2023 Date Revised 02.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/nar/gkad934 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. | ||
| 520 | |a The Msh2-Msh3 mismatch repair (MMR) complex in Saccharomyces cerevisiae recognizes and directs repair of insertion/deletion loops (IDLs) up to ∼17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR) and the DNA damage response. In contrast, Msh2-Msh3 promotes genome instability through trinucleotide repeat (TNR) expansions, presumably by binding structures that form from single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5' ssDNA flap structures interfered with Rad27 (Fen1 in humans)-mediated Okazaki fragment maturation (OFM) in vitro. Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and base excision repair in vivo. Elevated Msh2-Msh3 also induced a cell cycle arrest that was dependent on RAD9 and ELG1 and led to PCNA modification. These phenotypes also required Msh2-Msh3 ATPase activity and downstream MMR proteins, indicating an active mechanism that is not simply a result of Msh2-Msh3 DNA-binding activity. This study provides new mechanistic details regarding how excess Msh2-Msh3 can disrupt DNA replication and repair and highlights the role of Msh2-Msh3 protein abundance in Msh2-Msh3-mediated genomic instability | ||
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| 700 | 1 | |a Phelps, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Sridharan, Madhumita |e verfasserin |4 aut | |
| 700 | 1 | |a Becker, Jordan |e verfasserin |4 aut | |
| 700 | 1 | |a Lamb, Natalie A |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Charanya |e verfasserin |4 aut | |
| 700 | 1 | |a Sutton, Mark D |e verfasserin |4 aut | |
| 700 | 1 | |a Bielinsky, Anja |e verfasserin |4 aut | |
| 700 | 1 | |a Balakrishnan, Lata |e verfasserin |4 aut | |
| 700 | 1 | |a Surtees, Jennifer A |e verfasserin |4 aut | |
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