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XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells

Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt...

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Autores principales: Eckelmann, Bradley J, Bacolla, Albino, Wang, Haibo, Ye, Zu, Guerrero, Erika N, Jiang, Wei, El-Zein, Randa, Hegde, Muralidhar L, Tomkinson, Alan E, Tainer, John A, Mitra, Sankar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397735/
https://www.ncbi.nlm.nih.gov/pubmed/32776008
http://dx.doi.org/10.1093/narcan/zcaa013
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author Eckelmann, Bradley J
Bacolla, Albino
Wang, Haibo
Ye, Zu
Guerrero, Erika N
Jiang, Wei
El-Zein, Randa
Hegde, Muralidhar L
Tomkinson, Alan E
Tainer, John A
Mitra, Sankar
author_facet Eckelmann, Bradley J
Bacolla, Albino
Wang, Haibo
Ye, Zu
Guerrero, Erika N
Jiang, Wei
El-Zein, Randa
Hegde, Muralidhar L
Tomkinson, Alan E
Tainer, John A
Mitra, Sankar
author_sort Eckelmann, Bradley J
collection PubMed
description Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt-EJ factors, including XRCC1, PARP1 and POLQ, is synthetically lethal with BRCA2 deficiency; yet, XRCC1 roles in HR-deficient cancers and replication stress are enigmatic. Here, we show that after replication stress, XRCC1 forms an active repair complex with POLQ and MRE11 that supports alt-EJ activity in vitro. BRCA2 limits XRCC1 recruitment and repair complex formation to suppress alt-EJ at stalled forks. Without BRCA2 fork protection, XRCC1 enables cells to complete DNA replication at the expense of increased genome instability by promoting MRE11-dependent fork resection and restart. High XRCC1 and MRE11 gene expression negatively impacts Kaplan–Meier survival curves and hazard ratios for HR-deficient breast cancer patients in The Cancer Genome Atlas. The additive effects of depleting both BRCA2 and XRCC1 indicate distinct pathways for replication restart. Our collective data show that XRCC1-mediated processing contributes to replication fork degradation, replication restart and chromosome aberrations in BRCA2-deficient cells, uncovering new roles of XRCC1 and microhomology-mediated repair mechanisms in HR-deficient cancers, with implications for chemotherapeutic strategies targeting POLQ and PARP activities.
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spelling pubmed-73977352020-08-05 XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells Eckelmann, Bradley J Bacolla, Albino Wang, Haibo Ye, Zu Guerrero, Erika N Jiang, Wei El-Zein, Randa Hegde, Muralidhar L Tomkinson, Alan E Tainer, John A Mitra, Sankar NAR Cancer DNA Damage Sensing and Repair Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt-EJ factors, including XRCC1, PARP1 and POLQ, is synthetically lethal with BRCA2 deficiency; yet, XRCC1 roles in HR-deficient cancers and replication stress are enigmatic. Here, we show that after replication stress, XRCC1 forms an active repair complex with POLQ and MRE11 that supports alt-EJ activity in vitro. BRCA2 limits XRCC1 recruitment and repair complex formation to suppress alt-EJ at stalled forks. Without BRCA2 fork protection, XRCC1 enables cells to complete DNA replication at the expense of increased genome instability by promoting MRE11-dependent fork resection and restart. High XRCC1 and MRE11 gene expression negatively impacts Kaplan–Meier survival curves and hazard ratios for HR-deficient breast cancer patients in The Cancer Genome Atlas. The additive effects of depleting both BRCA2 and XRCC1 indicate distinct pathways for replication restart. Our collective data show that XRCC1-mediated processing contributes to replication fork degradation, replication restart and chromosome aberrations in BRCA2-deficient cells, uncovering new roles of XRCC1 and microhomology-mediated repair mechanisms in HR-deficient cancers, with implications for chemotherapeutic strategies targeting POLQ and PARP activities. Oxford University Press 2020-08-01 /pmc/articles/PMC7397735/ /pubmed/32776008 http://dx.doi.org/10.1093/narcan/zcaa013 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer. https://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/ (https://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 DNA Damage Sensing and Repair
Eckelmann, Bradley J
Bacolla, Albino
Wang, Haibo
Ye, Zu
Guerrero, Erika N
Jiang, Wei
El-Zein, Randa
Hegde, Muralidhar L
Tomkinson, Alan E
Tainer, John A
Mitra, Sankar
XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title_full XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title_fullStr XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title_full_unstemmed XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title_short XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells
title_sort xrcc1 promotes replication restart, nascent fork degradation and mutagenic dna repair in brca2-deficient cells
topic DNA Damage Sensing and Repair
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397735/
https://www.ncbi.nlm.nih.gov/pubmed/32776008
http://dx.doi.org/10.1093/narcan/zcaa013
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