Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions

James M. Daley (), Nozomi Tomimatsu, Grace Hooks, Weibin Wang, Adam S. Miller, Xiaoyu Xue, Kevin A. Nguyen, Hardeep Kaur, Elizabeth Williamson, Bipasha Mukherjee, Robert Hromas, Sandeep Burma () and Patrick Sung ()
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James M. Daley: Yale University School of Medicine
Nozomi Tomimatsu: University of Texas Health Science Center
Grace Hooks: Yale University School of Medicine
Weibin Wang: Yale University School of Medicine
Adam S. Miller: Yale University School of Medicine
Xiaoyu Xue: Yale University School of Medicine
Kevin A. Nguyen: Yale University School of Medicine
Hardeep Kaur: University of Texas Health Science Center
Elizabeth Williamson: University of Texas Health Science Center
Bipasha Mukherjee: University of Texas Health Science Center
Robert Hromas: University of Texas Health Science Center
Sandeep Burma: University of Texas Health Science Center
Patrick Sung: Yale University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract DNA double-strand break repair by homologous recombination begins with nucleolytic resection of the 5’ DNA strand at the break ends. Long-range resection is catalyzed by EXO1 and BLM-DNA2, which likely have to navigate through ribonucleotides and damaged bases. Here, we show that a short stretch of ribonucleotides at the 5’ terminus stimulates resection by EXO1. Ribonucleotides within a 5’ flap are resistant to cleavage by DNA2, and extended RNA:DNA hybrids inhibit both strand separation by BLM and resection by EXO1. Moreover, 8-oxo-guanine impedes EXO1 but enhances resection by BLM-DNA2, and an apurinic/apyrimidinic site stimulates resection by BLM-DNA2 and DNA strand unwinding by BLM. Accordingly, depletion of OGG1 or APE1 leads to greater dependence of DNA resection on DNA2. Importantly, RNase H2A deficiency impairs resection overall, which we attribute to the accumulation of long RNA:DNA hybrids at DNA ends. Our results help explain why eukaryotic cells possess multiple resection nucleases.

Date: 2020
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DOI: 10.1038/s41467-020-16903-4

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