PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F21%3A00123896" target="_blank" >RIV/00216224:14310/21:00123896 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.science.org/doi/10.1126/sciadv.abh1004" target="_blank" >https://www.science.org/doi/10.1126/sciadv.abh1004</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/sciadv.abh1004" target="_blank" >10.1126/sciadv.abh1004</a>

Jazyk výsledku

angličtina

Název v původním jazyce

PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

<a href="/cs/project/LM2018127" target="_blank" >LM2018127: Česká infrastruktura pro integrativní strukturní biologii</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Science Advances

ISSN

2375-2548

e-ISSN

—

Svazek periodika

7

Číslo periodika v rámci svazku

49

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

1-15

Kód UT WoS článku

000730595900005

EID výsledku v databázi Scopus

2-s2.0-85120666993