The Shu complex prevents mutagenesis and cytotoxicity of single-strand specific alkylation lesions

Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to h...

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Bibliographic Details
Published in:eLife 2021-11, Vol.10
Main Authors: Bonilla, Braulio, Brown, Alexander J, Hengel, Sarah R, Rapchak, Kyle S, Mitchell, Debra, Pressimone, Catherine A, Fagunloye, Adeola A, Luong, Thong T, Russell, Reagan A, Vyas, Rudri K, Mertz, Tony M, Zaher, Hani S, Mosammaparast, Nima, Malc, Ewa P, Mieczkowski, Piotr A, Roberts, Steven A, Bernstein, Kara A
Format: Article
Language:English
Subjects:
Adducts
alkyation damage
Alkylation
Biochemistry and Chemical Biology
Cell Biology
Cytosine
Cytotoxicity
DNA biosynthesis
DNA damage
DNA repair
Ectopic expression
Enzymes
Genomes
Homologous recombination
Homologous Recombination - drug effects
Methyl methanesulfonate
Methyl Methanesulfonate - pharmacology
Mutagenesis
Mutagens - pharmacology
Mutation
Rad51
Rad51 paralogs
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - metabolism
Shu complex
Single-stranded DNA
Transcription
Yeast
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Summary:Three-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries consistent with mutations resulting from 3meC. Ectopic expression of a human AlkB homolog in Shu-deficient yeast rescues MMS-induced growth defects and increased mutagenesis. Thus, our work identifies a novel homologous recombination-based mechanism mediated by the Shu complex for coping with alkylation adducts.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.68080