sciadv.abh1004.pdf (798.7 kB)
PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle
journal contribution
posted on 2023-06-10, 02:01 authored by Laura BaileyLaura Bailey, Rebecca Sarah Teague, Peter Kolesar, Lewis John Bainbridge, Howard D Lindsay, Aidan DohertyAidan DohertyReplication 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.
Funding
The role of a novel family of eukaryotic DNA polymerases in mitochondrial DNA replication; G0207; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/H019723/1
Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells; G1621; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/M008800/1
History
Publication status
- Published
File Version
- Published version
Journal
Science AdvancesISSN
2375-2548Publisher
American Association for the Advancement of ScienceExternal DOI
Issue
49Volume
7Page range
1-15Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-12-16First Open Access (FOA) Date
2021-12-16First Compliant Deposit (FCD) Date
2021-12-15Usage metrics
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