The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway

Joel C. Rosenbaum, Braulio Bonilla, Sarah R. Hengel, Tony M. Mertz, Benjamin W. Herken, Hinke G. Kazemier, Catherine A. Pressimone, Timothy C. Ratterman, Ellen MacNary, Alessio De Magis, Youngho Kwon, Stephen K. Godin, Bennett Van Houten, Daniel P. Normolle, Patrick Sung, Subha R. Das, Katrin Paeschke, Steven A. Roberts, Andrew P. VanDemark and Kara A. Bernstein ()
Additional contact information
Joel C. Rosenbaum: Department of Biological Sciences Pittsburgh
Braulio Bonilla: Department of Microbiology and Molecular Genetics
Sarah R. Hengel: Department of Microbiology and Molecular Genetics
Tony M. Mertz: College of Veterinary Medicine
Benjamin W. Herken: Department of Microbiology and Molecular Genetics
Hinke G. Kazemier: European Research Institute for the Biology of Ageing
Catherine A. Pressimone: Department of Microbiology and Molecular Genetics
Timothy C. Ratterman: Department of Chemistry and Center for Nucleic Acids Science & Technology
Ellen MacNary: College of Veterinary Medicine
Alessio De Magis: University Hospital Bonn
Youngho Kwon: Department of Molecular Biophysics and Biochemistry
Stephen K. Godin: Department of Microbiology and Molecular Genetics
Bennett Van Houten: Department of Pharmacology and Chemical Biology
Daniel P. Normolle: Department of Biostatistics
Patrick Sung: Department of Molecular Biophysics and Biochemistry
Subha R. Das: Department of Chemistry and Center for Nucleic Acids Science & Technology
Katrin Paeschke: European Research Institute for the Biology of Ageing
Steven A. Roberts: College of Veterinary Medicine
Andrew P. VanDemark: Department of Biological Sciences Pittsburgh
Kara A. Bernstein: Department of Microbiology and Molecular Genetics

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Accurate DNA replication is essential for genomic stability and cancer prevention. Homologous recombination is important for high-fidelity DNA damage tolerance during replication. How the homologous recombination machinery is recruited to replication intermediates is unknown. Here, we provide evidence that a Rad51 paralog-containing complex, the budding yeast Shu complex, directly recognizes and enables tolerance of predominantly lagging strand abasic sites. We show that the Shu complex becomes chromatin associated when cells accumulate abasic sites during S phase. We also demonstrate that purified recombinant Shu complex recognizes an abasic analog on a double-flap substrate, which prevents AP endonuclease activity and endonuclease-induced double-strand break formation. Shu complex DNA binding mutants are sensitive to methyl methanesulfonate, are not chromatin enriched, and exhibit increased mutation rates. We propose a role for the Shu complex in recognizing abasic sites at replication intermediates, where it recruits the homologous recombination machinery to mediate strand specific damage tolerance.

Date: 2019
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DOI: 10.1038/s41467-019-11374-8

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