Error-free DNA damage tolerance and sister chromatid proximity during DNA replication rely on the Polα/Primase/Ctf4 Complex
Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4...
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| Published in: | Molecular cell Vol. 57; no. 5; p. 812 |
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| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
05.03.2015
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| ISSN: | 1097-4164, 1097-4164 |
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| Abstract | Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4 mutants, proficient in bulk DNA replication, are defective in recombination-mediated damage-bypass by template switching (TS) and have reduced sister chromatid cohesion. The decrease in error-free DDT is accompanied by increased usage of mutagenic DDT, fork reversal, and higher rates of genome rearrangements mediated by faulty strand annealing. Notably, the DDT defects of Polα/Primase/Ctf4 mutants are not the consequence of increased sister chromatid distance, but are instead caused by altered single-stranded DNA metabolism and abnormal replication fork topology. We propose that error-free TS is driven by timely replicative helicase-coupled re-priming. Defects in this event impact on replication fork architecture and sister chromatid proximity, and represent a frequent source of chromosome lesions upon replication dysfunctions. |
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| AbstractList | Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4 mutants, proficient in bulk DNA replication, are defective in recombination-mediated damage-bypass by template switching (TS) and have reduced sister chromatid cohesion. The decrease in error-free DDT is accompanied by increased usage of mutagenic DDT, fork reversal, and higher rates of genome rearrangements mediated by faulty strand annealing. Notably, the DDT defects of Polα/Primase/Ctf4 mutants are not the consequence of increased sister chromatid distance, but are instead caused by altered single-stranded DNA metabolism and abnormal replication fork topology. We propose that error-free TS is driven by timely replicative helicase-coupled re-priming. Defects in this event impact on replication fork architecture and sister chromatid proximity, and represent a frequent source of chromosome lesions upon replication dysfunctions.Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4 mutants, proficient in bulk DNA replication, are defective in recombination-mediated damage-bypass by template switching (TS) and have reduced sister chromatid cohesion. The decrease in error-free DDT is accompanied by increased usage of mutagenic DDT, fork reversal, and higher rates of genome rearrangements mediated by faulty strand annealing. Notably, the DDT defects of Polα/Primase/Ctf4 mutants are not the consequence of increased sister chromatid distance, but are instead caused by altered single-stranded DNA metabolism and abnormal replication fork topology. We propose that error-free TS is driven by timely replicative helicase-coupled re-priming. Defects in this event impact on replication fork architecture and sister chromatid proximity, and represent a frequent source of chromosome lesions upon replication dysfunctions. Chromosomal replication is entwined with DNA damage tolerance (DDT) and chromatin structure establishment via elusive mechanisms. Here we examined how specific replication conditions affecting replisome architecture and repriming impact on DDT. We show that Saccharomyces cerevisiae Polα/Primase/Ctf4 mutants, proficient in bulk DNA replication, are defective in recombination-mediated damage-bypass by template switching (TS) and have reduced sister chromatid cohesion. The decrease in error-free DDT is accompanied by increased usage of mutagenic DDT, fork reversal, and higher rates of genome rearrangements mediated by faulty strand annealing. Notably, the DDT defects of Polα/Primase/Ctf4 mutants are not the consequence of increased sister chromatid distance, but are instead caused by altered single-stranded DNA metabolism and abnormal replication fork topology. We propose that error-free TS is driven by timely replicative helicase-coupled re-priming. Defects in this event impact on replication fork architecture and sister chromatid proximity, and represent a frequent source of chromosome lesions upon replication dysfunctions. |
| Author | Vanoli, Fabio Branzei, Dana Fumasoni, Marco Lopes, Massimo Zwicky, Katharina |
| Author_xml | – sequence: 1 givenname: Marco surname: Fumasoni fullname: Fumasoni, Marco organization: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy – sequence: 2 givenname: Katharina surname: Zwicky fullname: Zwicky, Katharina organization: Institute of Molecular Cancer Research, University of Zurich, CH-8057, Zurich, Switzerland – sequence: 3 givenname: Fabio surname: Vanoli fullname: Vanoli, Fabio organization: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy – sequence: 4 givenname: Massimo surname: Lopes fullname: Lopes, Massimo organization: Institute of Molecular Cancer Research, University of Zurich, CH-8057, Zurich, Switzerland – sequence: 5 givenname: Dana surname: Branzei fullname: Branzei, Dana email: dana.branzei@ifom.eu organization: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy. Electronic address: dana.branzei@ifom.eu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25661486$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Chromatids - genetics DNA Damage DNA Polymerase I - genetics DNA Polymerase I - metabolism DNA Primase - genetics DNA Primase - metabolism DNA Repair - genetics DNA Replication - genetics DNA, Single-Stranded - genetics DNA, Single-Stranded - metabolism DNA, Single-Stranded - ultrastructure DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism G2 Phase Cell Cycle Checkpoints - genetics Microscopy, Electron Models, Genetic Multiprotein Complexes - genetics Multiprotein Complexes - metabolism Mutation Recombination, Genetic Saccharomyces cerevisiae - genetics Saccharomyces cerevisiae - metabolism Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Signal Transduction - genetics Time Factors |
| Title | Error-free DNA damage tolerance and sister chromatid proximity during DNA replication rely on the Polα/Primase/Ctf4 Complex |
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