Evidence map›Paper›PMID 33932350›Full record

ArticleMolecular cell2021

Checkpoint-mediated DNA polymerase ε exonuclease activity curbing counteracts resection-driven fork collapse.

Grazia Pellicanò, Mohammed Al Mamun, Dolores Jurado-Santiago, Sara Villa-Hernández, Xingyu Yin, Michele Giannattasio, Michael C Lanz, Marcus B Smolka, Joseph Yeeles, Katsuhiko Shirahige and 2 more

Open access · greenAbstract read
In one paragraph

Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
1.3field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed, 22 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. DNA Damage and Replication Stress Checkpoints.Annual review of biochemistry · 2025
    Review
  5. Review
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress.BioEssays : news and reviews in molecular, cellular and developmental biology · 2022
    Article
  12. Review
  13. A mechanism for Rad53 to couple leading- and lagging-strand DNA synthesis under replication stress in budding yeast.Proceedings of the National Academy of Sciences of the United States of America · 2021
    Article
  14. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 6 institutions in 6 countries.

Grazia PellicanòCenter for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, Madrid, Spain.
Mohammed Al MamunCenter for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, Madrid, Spain.
Dolores Jurado-SantiagoCenter for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, Madrid, Spain.
Sara Villa-HernándezCenter for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, Madrid, Spain.
Xingyu YinDepartment of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.
Michele GiannattasioIFOM, the FIRC Institute of Molecular Oncology, Milan, Italy; Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
Michael C LanzWeill Institute for Cell and Molecular Biology Cornell University, Ithaca, NY, USA.
Marcus B SmolkaWeill Institute for Cell and Molecular Biology Cornell University, Ithaca, NY, USA.
Joseph YeelesMRC Laboratory of Molecular Biology, Cambridge, UK.
Katsuhiko ShirahigeInstitute for Quantitative Biosciences, University of Tokyo, Tokyo, Japan.
Miguel García-DíazDepartment of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.
Rodrigo BermejoCenter for Biological Research Margarita Salas (CIB-CSIC), Spanish National Research Council, Madrid, Spain. Electronic address: rodrigo.bermejo@csic.es.
Consejo Superior de Investigaciones Científicas · ESCornell University · USStony Brook University · USMRC Laboratory of Molecular Biology · GBThe University of Tokyo · JPUniversity of Milan · IT

Funding

Signaling Mechanisms in Genome Maintenance (Equipment Supplement 2023)R35GM141159 · NIGMS · CORNELL UNIVERSITY · PI Marcus Smolka · 2021 to 2026
$3.5M
Cellular Responses to DNA Replication StressR01GM097272 · NIGMS · CORNELL UNIVERSITY · PI SMOLKA, MARCUS · 2011 to 2020
$2.7M
Mechanisms of heterochromatin replicationR01GM123018 · NIGMS · CORNELL UNIVERSITY · PI SMOLKA, MARCUS · 2018 to 2021
$1.2M
Medical Research Council MC_UP_1201/12NIGMS NIH HHS R01 GM097272NIGMS NIH HHS R01 GM123018NIGMS NIH HHS R35 GM141159
6 · The paper itself

Abstract

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.

Indexed as

Amino Acid SubstitutionCatalytic DomainDNA, FungalDNA Polymerase IIExonucleasesMutation, MissenseSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsDNA, FungalDNA Polymerase IIExonucleasesSaccharomyces cerevisiae ProteinsDNA polymerase εDNA replication checkpointExo1 exonucleasegenome integrity maintenancenascent strand resectionpolymerase-exonuclease partitioningRad53(CHK1) kinasereplication fork stabilizationreplication stressreplisome phosphorylation

Identifiers

PMID33932350
PMCPMC7612761
OpenAlexW3159960544

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.