Work

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

Year: 2021

Type: article

Abstract: 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.

Source: eLife

DOI: 10.7554/elife.68080

Authors: Braulio Bonilla, Alexander J Brown, Sarah R Hengel, Kyle S Rapchak, Debra Mitchell, Catherine A Pressimone, Adeola A Fagunloye, Thong T Luong, Reagan A Russell, Rudri K Vyas, Tony M Mertz, Hani S Zaher, Nima Mosammaparast, Ewa P Malc, Piotr A Mieczkowski, Steven A Roberts, Kara A Bernstein

Institutions: University of Pittsburgh, Washington State University, Washington University in St. Louis, University of North Carolina at Chapel Hill

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $2,500

Funders: American Cancer Society, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences

Awards: G3083859175, Shu complex and RAD52 function in DNA damage recognition and subsequent repair, Ribosome stalling and activation of stress responses, A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE, Damaged RNA as a mediator of alkylation responses, Role of the Shu complex mediated protein interactions in genome maintenance, G5864344622, Training in Biotechnology: Emphasis in Protein Chemistry, Mechanisms of genome instability induced by APOBEC Cytidine Deaminases and its impacts during cancer development., Replication fork dynamics and repair by Rad51 paralogs after DNA alkylation, Cancer Center Support Grant

OpenAlex ID: W3152594323

FWCI: 0.39

Cites: 76

Cited by: 8

Related to: 10