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Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52
In vertebrates, genomic DNA double-strand breaks (DSBs) are removed by non-homologous end-joining processes: classical non-homologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ); or by homology-dependent processes: gene-conversion (GC) and single-strand annealing (SSA). Surprisingly, t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038941/ https://www.ncbi.nlm.nih.gov/pubmed/31832684 http://dx.doi.org/10.1093/nar/gkz1167 |
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author | Mladenov, Emil Staudt, Christian Soni, Aashish Murmann-Konda, Tamara Siemann-Loekes, Maria Iliakis, George |
author_facet | Mladenov, Emil Staudt, Christian Soni, Aashish Murmann-Konda, Tamara Siemann-Loekes, Maria Iliakis, George |
author_sort | Mladenov, Emil |
collection | PubMed |
description | In vertebrates, genomic DNA double-strand breaks (DSBs) are removed by non-homologous end-joining processes: classical non-homologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ); or by homology-dependent processes: gene-conversion (GC) and single-strand annealing (SSA). Surprisingly, these repair pathways are not real alternative options restoring genome integrity with equal efficiency, but show instead striking differences in speed, accuracy and cell-cycle-phase dependence. As a consequence, engagement of one pathway may be associated with processing-risks for the genome absent from another pathway. Characterization of engagement-parameters and their consequences is, therefore, essential for understanding effects on the genome of DSB-inducing agents, such as ionizing-radiation (IR). Here, by addressing pathway selection in G(2)-phase, we discover regulatory confinements in GC with consequences for SSA- and c-NHEJ-engagement. We show pronounced suppression of GC with increasing DSB-load that is not due to RAD51 availability and which is delimited but not defined by 53BP1 and RAD52. Strikingly, at low DSB-loads, GC repairs ∼50% of DSBs, whereas at high DSB-loads its contribution is undetectable. Notably, with increasing DSB-load and the associated suppression of GC, SSA gains ground, while alt-EJ is suppressed. These observations explain earlier, apparently contradictory results and advance our understanding of logic and mechanisms underpinning the wiring between DSB repair pathways. |
format | Online Article Text |
id | pubmed-7038941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-70389412020-03-02 Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 Mladenov, Emil Staudt, Christian Soni, Aashish Murmann-Konda, Tamara Siemann-Loekes, Maria Iliakis, George Nucleic Acids Res Genome Integrity, Repair and Replication In vertebrates, genomic DNA double-strand breaks (DSBs) are removed by non-homologous end-joining processes: classical non-homologous end-joining (c-NHEJ) and alternative end-joining (alt-EJ); or by homology-dependent processes: gene-conversion (GC) and single-strand annealing (SSA). Surprisingly, these repair pathways are not real alternative options restoring genome integrity with equal efficiency, but show instead striking differences in speed, accuracy and cell-cycle-phase dependence. As a consequence, engagement of one pathway may be associated with processing-risks for the genome absent from another pathway. Characterization of engagement-parameters and their consequences is, therefore, essential for understanding effects on the genome of DSB-inducing agents, such as ionizing-radiation (IR). Here, by addressing pathway selection in G(2)-phase, we discover regulatory confinements in GC with consequences for SSA- and c-NHEJ-engagement. We show pronounced suppression of GC with increasing DSB-load that is not due to RAD51 availability and which is delimited but not defined by 53BP1 and RAD52. Strikingly, at low DSB-loads, GC repairs ∼50% of DSBs, whereas at high DSB-loads its contribution is undetectable. Notably, with increasing DSB-load and the associated suppression of GC, SSA gains ground, while alt-EJ is suppressed. These observations explain earlier, apparently contradictory results and advance our understanding of logic and mechanisms underpinning the wiring between DSB repair pathways. Oxford University Press 2020-02-28 2019-12-13 /pmc/articles/PMC7038941/ /pubmed/31832684 http://dx.doi.org/10.1093/nar/gkz1167 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication Mladenov, Emil Staudt, Christian Soni, Aashish Murmann-Konda, Tamara Siemann-Loekes, Maria Iliakis, George Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title | Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title_full | Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title_fullStr | Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title_full_unstemmed | Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title_short | Strong suppression of gene conversion with increasing DNA double-strand break load delimited by 53BP1 and RAD52 |
title_sort | strong suppression of gene conversion with increasing dna double-strand break load delimited by 53bp1 and rad52 |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038941/ https://www.ncbi.nlm.nih.gov/pubmed/31832684 http://dx.doi.org/10.1093/nar/gkz1167 |
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