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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...

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Autores principales: Mladenov, Emil, Staudt, Christian, Soni, Aashish, Murmann-Konda, Tamara, Siemann-Loekes, Maria, Iliakis, George
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
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.
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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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