Evidence map›Paper›PMID 34624216›Full record

ArticleMolecular cell2021

Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.

Stephanie Tirman, Annabel Quinet, Matthew Wood, Alice Meroni, Emily Cybulla, Jessica Jackson, Silvia Pegoraro, Antoine Simoneau, Lee Zou, Alessandro Vindigni

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 128 papers.

0numbers the graph read from it
0cells of the map it votes in
128citing papers in PubMed
11.1field-weighted citation impact, top 1% 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

128 citing papers in PubMed, 182 citations in OpenAlex.

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68 more citing papers are in PubMed but not listed here.

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

10 authors at 2 institutions in 1 country.

Stephanie TirmanDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Annabel QuinetDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Matthew WoodDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Alice MeroniDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Emily CybullaDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Jessica JacksonDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Silvia PegoraroDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Antoine SimoneauMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Lee ZouMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Alessandro VindigniDivision of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: avindigni@wustl.edu.
Washington University in St. Louis · USHarvard University · US

Funding

Mechanisms of replication fork protection and recoveryR01CA248526 · NCI · WASHINGTON UNIVERSITY · PI Alessandro Vindigni, Lee Zou · 2020 to 2026
$3.6M
Replication fork repriming versus reversalR01CA237263 · NCI · WASHINGTON UNIVERSITY · PI Alessandro Vindigni · 2019 to 2026
$3.0M
Targeting Rad18-dependent replication stress pathways to modulate chemoresponse in BRCA1-deficient cancersF30CA254215 · NCI · SAINT LOUIS UNIVERSITY · PI CYBULLA, EMILY · 2020 to 2023
$167k
NCI NIH HHS F30 CA254215NCI NIH HHS R01 CA237263NCI NIH HHS R01 CA248526
6 · The paper itself

Abstract

PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill the ssDNA gaps generated in cisplatin-treated cells upon increased PRIMPOL expression or when replication fork reversal is defective because of SMARCAL1 inactivation or PARP inhibition. We found that a mechanism dependent on the E3 ubiquitin ligase RAD18, PCNA monoubiquitination, and the REV1 and POLζ translesion synthesis polymerases promotes gap filling in G2. The E2-conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are instead responsible for gap filling in S, suggesting that temporally distinct pathways of gap filling operate throughout the cell cycle. Furthermore, we found that BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity and that simultaneously targeting fork reversal and gap filling enhances chemosensitivity in BRCA-deficient cells.

Indexed as

DNA Breaks, Single-StrandedDNA RepairDNA ReplicationG2 PhaseS PhaseAntineoplastic AgentsBRCA1 ProteinBRCA2 ProteinCell Line, TumorDNA-Binding ProteinsDNA-Directed DNA PolymeraseDNA HelicasesDNA, NeoplasmDNA PrimaseGenomic InstabilityHEK293 CellsAntineoplastic AgentsBRCA1 ProteinBRCA1 protein, humanBRCA2 ProteinBRCA2 protein, humanDNA-Binding ProteinsDNA-Directed DNA PolymeraseDNA HelicasesDNA, NeoplasmDNA PrimaseMRE11 Homologue ProteinMRE11 protein, humanMultifunctional EnzymesNucleotidyltransferasesPCNA protein, humanPrimPol protein, humanProliferating Cell Nuclear AntigenRAD18 protein, humanREV1 protein, humanREV3L protein, humanSMARCAL1 protein, humanUBE2N protein, humanUbiquitin-Conjugating EnzymesUbiquitin-Protein LigasesY-Family DNA PolymerasesBRCA1BRCA2DNA damage toleranceDNA replicationgenome stabilitypost-replicative repairPRIMPOLreplication stressssDNA gapstranslesion synthesis polymerases

Identifiers

PMID34624216
PMCPMC8555837
OpenAlexW3203739989

What OpenQuestion 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 OpenQuestion graph.