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

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The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway.
Nature Communications ( IF 14.7 ) Pub Date : 2019-08-05 , DOI: 10.1038/s41467-019-11374-8
Joel C Rosenbaum ₁ , Braulio Bonilla ₂ , Sarah R Hengel ₂ , Tony M Mertz ₃ , Benjamin W Herken ₂ , Hinke G Kazemier ₄ , Catherine A Pressimone ₂ , Timothy C Ratterman ₅ , Ellen MacNary ₃ , Alessio De Magis ₆ , Youngho Kwon _{7,

8} , Stephen K Godin ₂ , Bennett Van Houten ₉ , Daniel P Normolle ₁₀ , Patrick Sung _{7,

8} , Subha R Das ₅ , Katrin Paeschke _{4,

6} , Steven A Roberts ₃ , Andrew P VanDemark ₁ , Kara A Bernstein ₂

Affiliation

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

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.

中文翻译：

Rad51旁系同源物促进了新的DNA链特异性损伤耐受途径。

准确的DNA复制对于基因组稳定性和癌症预防至关重要。同源重组对于复制过程中高保真DNA损伤耐受性很重要。同源重组机制如何募集到复制中间体尚不清楚。在这里，我们提供的证据表明，含有Rad51旁系同源物的复合物，即发芽的酵母Shu复合物，可以直接识别并允许主要滞后的链无碱基位点。我们显示，当细胞在S期积累无碱基位点时，Shu复合物变得与染色质相关。我们还证明，纯化的重组Shu复合物可识别双瓣底物上的无碱基类似物，从而阻止AP核酸内切酶活性和核酸内切酶诱导的双链断裂形成。Shu复杂的DNA结合突变体对甲磺酸甲酯敏感，没有染色质富集，并表现出增加的突变率。我们提出了舒复合物在识别复制中间体的无碱基位点中的作用，在该处它募集了同源重组机制来介导链特异性损伤耐受性。

更新日期：2019-08-05

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