Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors

Sung Bau Lee, Sandra Segura-Bayona, Marina Villamor-Payà, Giulia Saredi, Matthew A.M. Todd, Camille Stephan Otto Attolini, Ting Yu Chang, Travis H. Stracker, Anja Groth

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G1. We find that deficient replication-coupled de novo nucleosome assembly renders replication forks unstable and highly dependent on the ATR and CHK1 checkpoint kinases, as well as poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) activity, to avoid collapse. Human cancer data revealed frequent up-regulation of TLK genes and an association with poor patient outcome in multiple types of cancer, and depletion of TLK activity leads to increased replication stress and DNA damage in a panel of cancer cells. Our results reveal a critical role for TLKs in chromatin replication and suppression of replication stress and identify a synergistic lethal relationship with checkpoint signaling and PARP that could be exploited in treatment of a broad range of cancers.

Original languageEnglish
Article numbereaat4985
JournalScience advances
Volume4
Issue number8
DOIs
Publication statusPublished - Aug 8 2018

Fingerprint

Adenosine
Phosphotransferases
Chromatin Assembly and Disassembly
Nucleosomes
DNA Replication
DNA Damage
Chromatin
Neoplasms
G1 Phase Cell Cycle Checkpoints
Single-Stranded DNA
Epigenomics
Cell Division
Up-Regulation
Maintenance
Phenotype
Synthetic Lethal Mutations
Genes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Lee, S. B., Segura-Bayona, S., Villamor-Payà, M., Saredi, G., Todd, M. A. M., Attolini, C. S. O., ... Groth, A. (2018). Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Science advances, 4(8), [eaat4985]. https://doi.org/10.1126/sciadv.aat4985

Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. / Lee, Sung Bau; Segura-Bayona, Sandra; Villamor-Payà, Marina; Saredi, Giulia; Todd, Matthew A.M.; Attolini, Camille Stephan Otto; Chang, Ting Yu; Stracker, Travis H.; Groth, Anja.

In: Science advances, Vol. 4, No. 8, eaat4985, 08.08.2018.

Research output: Contribution to journalArticle

Lee, SB, Segura-Bayona, S, Villamor-Payà, M, Saredi, G, Todd, MAM, Attolini, CSO, Chang, TY, Stracker, TH & Groth, A 2018, 'Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors', Science advances, vol. 4, no. 8, eaat4985. https://doi.org/10.1126/sciadv.aat4985
Lee, Sung Bau ; Segura-Bayona, Sandra ; Villamor-Payà, Marina ; Saredi, Giulia ; Todd, Matthew A.M. ; Attolini, Camille Stephan Otto ; Chang, Ting Yu ; Stracker, Travis H. ; Groth, Anja. / Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. In: Science advances. 2018 ; Vol. 4, No. 8.
@article{46366f7608164a17ad612284d0a00fbe,
title = "Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors",
abstract = "DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G1. We find that deficient replication-coupled de novo nucleosome assembly renders replication forks unstable and highly dependent on the ATR and CHK1 checkpoint kinases, as well as poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) activity, to avoid collapse. Human cancer data revealed frequent up-regulation of TLK genes and an association with poor patient outcome in multiple types of cancer, and depletion of TLK activity leads to increased replication stress and DNA damage in a panel of cancer cells. Our results reveal a critical role for TLKs in chromatin replication and suppression of replication stress and identify a synergistic lethal relationship with checkpoint signaling and PARP that could be exploited in treatment of a broad range of cancers.",
author = "Lee, {Sung Bau} and Sandra Segura-Bayona and Marina Villamor-Pay{\`a} and Giulia Saredi and Todd, {Matthew A.M.} and Attolini, {Camille Stephan Otto} and Chang, {Ting Yu} and Stracker, {Travis H.} and Anja Groth",
year = "2018",
month = "8",
day = "8",
doi = "10.1126/sciadv.aat4985",
language = "English",
volume = "4",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "8",

}

TY - JOUR

T1 - Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors

AU - Lee, Sung Bau

AU - Segura-Bayona, Sandra

AU - Villamor-Payà, Marina

AU - Saredi, Giulia

AU - Todd, Matthew A.M.

AU - Attolini, Camille Stephan Otto

AU - Chang, Ting Yu

AU - Stracker, Travis H.

AU - Groth, Anja

PY - 2018/8/8

Y1 - 2018/8/8

N2 - DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G1. We find that deficient replication-coupled de novo nucleosome assembly renders replication forks unstable and highly dependent on the ATR and CHK1 checkpoint kinases, as well as poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) activity, to avoid collapse. Human cancer data revealed frequent up-regulation of TLK genes and an association with poor patient outcome in multiple types of cancer, and depletion of TLK activity leads to increased replication stress and DNA damage in a panel of cancer cells. Our results reveal a critical role for TLKs in chromatin replication and suppression of replication stress and identify a synergistic lethal relationship with checkpoint signaling and PARP that could be exploited in treatment of a broad range of cancers.

AB - DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G1. We find that deficient replication-coupled de novo nucleosome assembly renders replication forks unstable and highly dependent on the ATR and CHK1 checkpoint kinases, as well as poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) activity, to avoid collapse. Human cancer data revealed frequent up-regulation of TLK genes and an association with poor patient outcome in multiple types of cancer, and depletion of TLK activity leads to increased replication stress and DNA damage in a panel of cancer cells. Our results reveal a critical role for TLKs in chromatin replication and suppression of replication stress and identify a synergistic lethal relationship with checkpoint signaling and PARP that could be exploited in treatment of a broad range of cancers.

UR - http://www.scopus.com/inward/record.url?scp=85051404535&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051404535&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aat4985

DO - 10.1126/sciadv.aat4985

M3 - Article

VL - 4

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 8

M1 - eaat4985

ER -