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; Kara A. Bernstein

doi:10.1038/s41467-019-11374-8

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, Kara A. Bernstein

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21 Scopus citations

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.

Original language	English (US)
Article number	3515
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11374-8
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Rosenbaum, J. C., Bonilla, B., Hengel, S. R., Mertz, T. M., Herken, B. W., Kazemier, H. G., Pressimone, C. A., Ratterman, T. C., MacNary, E., De Magis, A., Kwon, Y., Godin, S. K., Van Houten, B., Normolle, D. P., Sung, P., Das, S. R., Paeschke, K., Roberts, S. A., VanDemark, A. P., & Bernstein, K. A. (2019). The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway. Nature communications, 10(1), Article 3515. https://doi.org/10.1038/s41467-019-11374-8

Rosenbaum, JC, Bonilla, B, Hengel, SR, Mertz, TM, Herken, BW, Kazemier, HG, Pressimone, CA, Ratterman, TC, MacNary, E, De Magis, A, Kwon, Y, Godin, SK, Van Houten, B, Normolle, DP, Sung, P, Das, SR, Paeschke, K, Roberts, SA, VanDemark, AP & Bernstein, KA 2019, 'The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway', Nature communications, vol. 10, no. 1, 3515. https://doi.org/10.1038/s41467-019-11374-8

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title = "The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway",

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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AU - Das, Subha R.

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AU - Roberts, Steven A.

AU - VanDemark, Andrew P.

AU - Bernstein, Kara A.

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N2 - 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.

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

Abstract

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