PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

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Authors	BAILEY Laura J. TEAGUE Rebecca KOLESÁR Peter BAINBRIDGE Lewis J. LINDSAY Howard D. DOHERTY Aidan J.
Year of publication	2021
Type	Article in Periodical
Magazine / Source	Science Advances
MU Faculty or unit	Faculty of Science
Citation
Web	https://www.science.org/doi/10.1126/sciadv.abh1004
Doi	http://dx.doi.org/10.1126/sciadv.abh1004
Keywords	POLO-LIKE KINASE-1; MITOCHONDRIAL-DNA REPLICATION; FORK REVERSAL; POLYMERASE ETA; PHOSPHORYLATION; CATASTROPHE; BYPASS; REPAIR; DOMAIN; ROLES
Description	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.
Related projects:	Czech Infrastructure for Integrative Structural Biology