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Título: | Checkpoint-mediated DNA polymerase ε exonuclease activity curbing counteracts resection-driven fork collapse |
Autor: | Pellicanò, Grazia CSIC ; Al Mamun, Mohammed CSIC ORCID; Jurado-Santiago, Dolores CSIC; Villa, Sara CSIC; Yin, Xingyu; Bermejo, Rodrigo CSIC ORCID CVN | Palabras clave: | DNA polymerase ε Polymerase-exonuclease partitioning Nascent strand resection Replisome phosphorylation Replication stress DNA replication checkpoint Replication fork stabilization Genome integrity maintenance Rad53CHK1 kinase Exo1 exonuclease |
Fecha de publicación: | 30-abr-2021 | Editor: | Cell Press | Citación: | Molecular Cell 81: 1-15 (2021) | Resumen: | DNA polymerase ε (Polε) carries out high-fidelity leading strand synthesis owing to its exonuclease activity. Polε polymerase and exonuclease activities are balanced, because of partitioning of nascent DNA strands between catalytic sites, so that net resection occurs when synthesis is impaired. In vivo, DNA synthesis stalling activates replication checkpoint kinases, which act to preserve the functional integrity of replication forks. We show that stalled Polε drives nascent strand resection causing fork functional collapse, averted via checkpoint-dependent phosphorylation. Polε catalytic subunit Pol2 is phosphorylated on serine 430, influencing partitioning between polymerase and exonuclease active sites. A phosphormimetic S430D change reduces exonucleolysis in vitro and counteracts fork collapse. Conversely, non-phosphorylatable pol2-S430A expression causes resection-driven stressed fork defects. Our findings reveal that checkpoint kinases switch Polε to an exonuclease-safe mode preventing nascent strand resection and stabilizing stalled replication forks. Elective partitioning suppression has implications for the diverse Polε roles in genome integrity maintenance. | Descripción: | 62 p.-7 fig.-1 tab.-7 fig. suppl.-1 tab.supl. | Versión del editor: | https://doi.org/10.1016/j.molcel.2021.04.006 | URI: | http://hdl.handle.net/10261/239827 | DOI: | 10.1016/j.molcel.2021.04.006 | ISSN: | 1097-2765 | E-ISSN: | 1097-4164 |
Aparece en las colecciones: | (CIB) Artículos |
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Pellicanó et al Mol Cell 2021.pdf | 49,61 MB | Adobe PDF | Visualizar/Abrir |
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