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PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

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PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. / Bailey, L.J.; Teague, R.; Kolesar, P. et al.
In: Science Advances, Vol. 7, No. 49, eabh1004, 03.12.2021.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Bailey, LJ, Teague, R, Kolesar, P, Bainbridge, LJ, Lindsay, HD & Doherty, AJ 2021, 'PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle', Science Advances, vol. 7, no. 49, eabh1004. https://doi.org/10.1126/sciadv.abh1004

APA

Bailey, L. J., Teague, R., Kolesar, P., Bainbridge, L. J., Lindsay, H. D., & Doherty, A. J. (2021). PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. Science Advances, 7(49), Article eabh1004. https://doi.org/10.1126/sciadv.abh1004

Vancouver

Bailey LJ, Teague R, Kolesar P, Bainbridge LJ, Lindsay HD, Doherty AJ. PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. Science Advances. 2021 Dec 3;7(49):eabh1004. doi: 10.1126/sciadv.abh1004

Author

Bailey, L.J. ; Teague, R. ; Kolesar, P. et al. / PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. In: Science Advances. 2021 ; Vol. 7, No. 49.

Bibtex

@article{08f9138bc15342c0acd76eea23a95022,
title = "PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle",
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{\textquoteright}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. ",
keywords = "Cytology, Damage tolerance, Binding motif, Cell cycle, Conserved residues, DNA damages, Genome duplication, Human cells, Lesion bypass, Polo-like kinase 1, Replication fork, S-phase, Phosphorylation",
author = "L.J. Bailey and R. Teague and P. Kolesar and L.J. Bainbridge and H.D. Lindsay and A.J. Doherty",
year = "2021",
month = dec,
day = "3",
doi = "10.1126/sciadv.abh1004",
language = "English",
volume = "7",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "49",

}

RIS

TY - JOUR

T1 - PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle

AU - Bailey, L.J.

AU - Teague, R.

AU - Kolesar, P.

AU - Bainbridge, L.J.

AU - Lindsay, H.D.

AU - Doherty, A.J.

PY - 2021/12/3

Y1 - 2021/12/3

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.

AB - 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.

KW - Cytology

KW - Damage tolerance

KW - Binding motif

KW - Cell cycle

KW - Conserved residues

KW - DNA damages

KW - Genome duplication

KW - Human cells

KW - Lesion bypass

KW - Polo-like kinase 1

KW - Replication fork

KW - S-phase

KW - Phosphorylation

U2 - 10.1126/sciadv.abh1004

DO - 10.1126/sciadv.abh1004

M3 - Journal article

VL - 7

JO - Science Advances

JF - Science Advances

SN - 2375-2548

IS - 49

M1 - eabh1004

ER -