PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

Bailey, Laura J, Teague, Rebecca, Kolesar, Peter, Bainbridge, Lewis J, Lindsay, Howard D and Doherty, Aidan J (2021) PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. Science Advances, 7 (49). pp. 1-15. ISSN 2375-2548

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Abstract

Replication stress and DNA damage stall replication forks and impede genome synthesis. During S phase, damage tolerance pathways allow lesion bypass to ensure efficient genome duplication. One such pathway is repriming, mediated by Primase-Polymerase (PrimPol) in human cells. However, the mechanisms by which PrimPol is regulated are poorly understood. Here, we demonstrate that PrimPol is phosphorylated by Polo-like kinase 1 (PLK1) at a conserved residue between PrimPol’s RPA binding motifs. This phosphorylation is differentially modified throughout the cell cycle, which prevents aberrant recruitment of PrimPol to chromatin. Phosphorylation can also be delayed and reversed in response to replication stress. The absence of PLK1-dependent regulation of PrimPol induces phenotypes including chromosome breaks, micronuclei, and decreased survival after treatment with camptothecin, olaparib, and UV-C. Together, these findings establish that deregulated repriming leads to genomic instability, highlighting the importance of regulating this damage tolerance pathway following fork stalling and throughout the cell cycle.

Item Type: Article
Keywords: Primase, PrimPol, Repriming, DNA Replication, Replication stress, PLK1, damage tolerance
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Aidan Doherty
Date Deposited: 16 Dec 2021 08:21
Last Modified: 16 Dec 2021 08:30
URI: http://sro.sussex.ac.uk/id/eprint/103390

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Project NameSussex Project NumberFunderFunder Ref
The role of a novel family of eukaryotic DNA polymerases in mitochondrial DNA replicationG0207BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/H019723/1
Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cellsG1621BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/M008800/1