Abstract
DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication-associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Chromatids / genetics
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Chromatids / ultrastructure
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Chromatin / ultrastructure
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Chromosomes, Fungal / genetics
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Chromosomes, Fungal / ultrastructure*
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DNA Damage*
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DNA Helicases / metabolism
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DNA Replication
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DNA, Cruciform
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DNA, Fungal / drug effects
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DNA, Fungal / genetics*
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Genomic Instability
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High Mobility Group Proteins / chemistry
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High Mobility Group Proteins / genetics
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High Mobility Group Proteins / physiology*
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Methyl Methanesulfonate / pharmacology
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Mutagens / pharmacology
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Proliferating Cell Nuclear Antigen / metabolism
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Replication Protein A / metabolism
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S Phase
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Saccharomyces cerevisiae Proteins / physiology*
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination
Substances
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Chromatin
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DNA, Cruciform
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DNA, Fungal
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HMO1 protein, S cerevisiae
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High Mobility Group Proteins
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MMS2 protein, S cerevisiae
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Mutagens
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POL30 protein, S cerevisiae
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Proliferating Cell Nuclear Antigen
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RFA1 protein, S cerevisiae
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Replication Protein A
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Saccharomyces cerevisiae Proteins
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Methyl Methanesulfonate
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UBC13 protein, S cerevisiae
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Ubiquitin-Conjugating Enzymes
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Ubiquitin-Protein Ligases
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RAD5 protein, S cerevisiae
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DNA Helicases