PLK1 regulates the PrimPol damage tolerance pathway during the
cell cycle

J 2021

PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

BAILEY, Laura J., Rebecca TEAGUE, Peter KOLESÁR, Lewis J. BAINBRIDGE, Howard D. LINDSAY et. al.

Basic information

Original name

PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

Authors

BAILEY, Laura J., Rebecca TEAGUE, Peter KOLESÁR (703 Slovakia, belonging to the institution), Lewis J. BAINBRIDGE, Howard D. LINDSAY and Aidan J. DOHERTY (guarantor)

Edition

Science Advances, New York, American Association for the Advancement of Science, 2021, 2375-2548

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10603 Genetics and heredity

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 14.957

RIV identification code

RIV/00216224:14310/21:00123896

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1126/sciadv.abh1004

UT WoS

000730595900005

Keywords in English

POLO-LIKE KINASE-1; MITOCHONDRIAL-DNA REPLICATION; FORK REVERSAL; POLYMERASE ETA; PHOSPHORYLATION; CATASTROPHE; BYPASS; REPAIR; DOMAIN; ROLES

Abstract

V originále

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.

Links

LM2018127, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

BAILEY, Laura J., Rebecca TEAGUE, Peter KOLESÁR, Lewis J. BAINBRIDGE, Howard D. LINDSAY and Aidan J. DOHERTY. PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. Science Advances. New York: American Association for the Advancement of Science, 2021, vol. 7, No 49, p. 1-15. ISSN 2375-2548. Available from: https://dx.doi.org/10.1126/sciadv.abh1004.

@article{1825003,
   author = {Bailey, Laura J. and Teague, Rebecca and Kolesár, Peter and Bainbridge, Lewis J. and Lindsay, Howard D. and Doherty, Aidan J.},
   article_location = {New York},
   article_number = {49},
   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},
   language = {eng},
   issn = {2375-2548},
   journal = {Science Advances},
   title = {PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle},
   url = {https://www.science.org/doi/10.1126/sciadv.abh1004},
   volume = {7},
   year = {2021}
}

TY  - JOUR
ID  - 1825003
AU  - Bailey, Laura J. - Teague, Rebecca - Kolesár, Peter - Bainbridge, Lewis J. - Lindsay, Howard D. - Doherty, Aidan J.
PY  - 2021
TI  - PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle
JF  - Science Advances
VL  - 7
IS  - 49
SP  - 1-15
EP  - 1-15
PB  - American Association for the Advancement of Science
SN  - 23752548
KW  - POLO-LIKE KINASE-1
KW  - MITOCHONDRIAL-DNA REPLICATION
KW  - FORK REVERSAL
KW  - POLYMERASE ETA
KW  - PHOSPHORYLATION
KW  - CATASTROPHE
KW  - BYPASS
KW  - REPAIR
KW  - DOMAIN
KW  - ROLES
UR  - https://www.science.org/doi/10.1126/sciadv.abh1004
N2  - 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.
ER  -

BAILEY, Laura J., Rebecca TEAGUE, Peter KOLESÁR, Lewis J. BAINBRIDGE, Howard D. LINDSAY and Aidan J. DOHERTY. PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. \textit{Science Advances}. New York: American Association for the Advancement of Science, 2021, vol.~7, No~49, p.~1-15. ISSN~2375-2548. Available from: https://dx.doi.org/10.1126/sciadv.abh1004.

Detailed Information on Publication Record