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

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...

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Autores principales: Daley, James M., Tomimatsu, Nozomi, Hooks, Grace, Wang, Weibin, Miller, Adam S., Xue, Xiaoyu, Nguyen, Kevin A., Kaur, Hardeep, Williamson, Elizabeth, Mukherjee, Bipasha, Hromas, Robert, Burma, Sandeep, Sung, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303207/
https://www.ncbi.nlm.nih.gov/pubmed/32555206
http://dx.doi.org/10.1038/s41467-020-16903-4
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author Daley, James M.
Tomimatsu, Nozomi
Hooks, Grace
Wang, Weibin
Miller, Adam S.
Xue, Xiaoyu
Nguyen, Kevin A.
Kaur, Hardeep
Williamson, Elizabeth
Mukherjee, Bipasha
Hromas, Robert
Burma, Sandeep
Sung, Patrick
author_facet Daley, James M.
Tomimatsu, Nozomi
Hooks, Grace
Wang, Weibin
Miller, Adam S.
Xue, Xiaoyu
Nguyen, Kevin A.
Kaur, Hardeep
Williamson, Elizabeth
Mukherjee, Bipasha
Hromas, Robert
Burma, Sandeep
Sung, Patrick
author_sort Daley, James M.
collection PubMed
description 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.
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spelling pubmed-73032072020-06-22 Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions Daley, James M. Tomimatsu, Nozomi Hooks, Grace Wang, Weibin Miller, Adam S. Xue, Xiaoyu Nguyen, Kevin A. Kaur, Hardeep Williamson, Elizabeth Mukherjee, Bipasha Hromas, Robert Burma, Sandeep Sung, Patrick Nat Commun Article 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. Nature Publishing Group UK 2020-06-18 /pmc/articles/PMC7303207/ /pubmed/32555206 http://dx.doi.org/10.1038/s41467-020-16903-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Daley, James M.
Tomimatsu, Nozomi
Hooks, Grace
Wang, Weibin
Miller, Adam S.
Xue, Xiaoyu
Nguyen, Kevin A.
Kaur, Hardeep
Williamson, Elizabeth
Mukherjee, Bipasha
Hromas, Robert
Burma, Sandeep
Sung, Patrick
Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title_full Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title_fullStr Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title_full_unstemmed Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title_short Specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
title_sort specificity of end resection pathways for double-strand break regions containing ribonucleotides and base lesions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303207/
https://www.ncbi.nlm.nih.gov/pubmed/32555206
http://dx.doi.org/10.1038/s41467-020-16903-4
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