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Nat Commun. 2019 Aug 5;10(1):3515. doi: 10.1038/s41467-019-11374-8.

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

Author information

1
University of Pittsburgh, Department of Biological Sciences Pittsburgh, Pittsburgh, PA, 15260, USA.
2
University of Pittsburgh, School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA, 15213, USA.
3
Washington State University, School of Molecular Biosciences and Center for Reproductive Biology, College of Veterinary Medicine, Pullman, WA, 99164, USA.
4
University of Groningen, University Medical Center Groningen, European Research Institute for the Biology of Ageing, 9713 AV, Groningen, Netherlands.
5
Carnegie Mellon University, Department of Chemistry and Center for Nucleic Acids Science & Technology, Pittsburgh, PA, 15213, USA.
6
Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
7
Yale University, School of Medicine, Department of Molecular Biophysics and Biochemistry, New Haven, CT, 06511, USA.
8
University of Texas Health Science Center at San Antonio, Department of Biochemistry and Structural Biology, San Antonio, TX, 78229, USA.
9
University of Pittsburgh, School of Medicine, Department of Pharmacology and Chemical Biology, Pittsburgh, PA, 15213, USA.
10
University of Pittsburgh, School of Public Health, Department of Biostatistics, Pittsburgh, PA, 15261, USA.
11
University of Pittsburgh, School of Medicine, Department of Microbiology and Molecular Genetics, Pittsburgh, PA, 15213, USA. karab@pitt.edu.

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.

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