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Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase
DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072374/ https://www.ncbi.nlm.nih.gov/pubmed/35513396 http://dx.doi.org/10.1038/s41467-022-30215-9 |
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author | Joseph, Chinnu Rose Dusi, Sabrina Giannattasio, Michele Branzei, Dana |
author_facet | Joseph, Chinnu Rose Dusi, Sabrina Giannattasio, Michele Branzei, Dana |
author_sort | Joseph, Chinnu Rose |
collection | PubMed |
description | DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling. |
format | Online Article Text |
id | pubmed-9072374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90723742022-05-07 Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase Joseph, Chinnu Rose Dusi, Sabrina Giannattasio, Michele Branzei, Dana Nat Commun Article DNA damage tolerance (DDT), activated by replication stress during genome replication, is mediated by translesion synthesis and homologous recombination (HR). Here we uncover that DDK kinase, essential for replication initiation, is critical for replication-associated recombination-mediated DDT. DDK relies on its multi-monoSUMOylation to facilitate HR-mediated DDT and optimal retention of Rad51 recombinase at replication damage sites. Impairment of DDK kinase activity, reduced monoSUMOylation and mutations in the putative SUMO Interacting Motifs (SIMs) of Rad51 impair replication-associated recombination and cause fork uncoupling with accumulation of large single-stranded DNA regions at fork branching points. Notably, genetic activation of salvage recombination rescues the uncoupled fork phenotype but not the recombination-dependent gap-filling defect of DDK mutants, revealing that the salvage recombination pathway operates preferentially proximal to fork junctions at stalled replication forks. Overall, we uncover that monoSUMOylated DDK acts with Rad51 in an axis that prevents replication fork uncoupling and mediates recombination-dependent gap-filling. Nature Publishing Group UK 2022-05-05 /pmc/articles/PMC9072374/ /pubmed/35513396 http://dx.doi.org/10.1038/s41467-022-30215-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Joseph, Chinnu Rose Dusi, Sabrina Giannattasio, Michele Branzei, Dana Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title | Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title_full | Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title_fullStr | Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title_full_unstemmed | Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title_short | Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase |
title_sort | rad51-mediated replication of damaged templates relies on monosumoylated ddk kinase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072374/ https://www.ncbi.nlm.nih.gov/pubmed/35513396 http://dx.doi.org/10.1038/s41467-022-30215-9 |
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