Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors
(2018) In Science Advances 4(8).- 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... (More)
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.
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- author
- Lee, Sung Bau ; Segura-Bayona, Sandra ; Villamor-Payà, Marina ; Saredi, Giulia LU ; Todd, Matthew A.M. ; Attolini, Camille Stephan Otto ; Chang, Ting Yu ; Stracker, Travis H. and Groth, Anja
- publishing date
- 2018-08-08
- type
- Contribution to journal
- publication status
- published
- in
- Science Advances
- volume
- 4
- issue
- 8
- article number
- eaat4985
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- scopus:85051404535
- pmid:30101194
- ISSN
- 2375-2548
- DOI
- 10.1126/sciadv.aat4985
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: Copyright © 2018 The Authors.
- id
- ced2ae3a-f2f7-4f7c-aaf0-cc6555412a1f
- date added to LUP
- 2025-11-03 11:16:41
- date last changed
- 2025-11-17 12:22:29
@article{ced2ae3a-f2f7-4f7c-aaf0-cc6555412a1f,
abstract = {{<p>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 G<sub>1</sub>. 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.</p>}},
author = {{Lee, Sung Bau and Segura-Bayona, Sandra and Villamor-Payà, Marina and Saredi, Giulia and Todd, Matthew A.M. and Attolini, Camille Stephan Otto and Chang, Ting Yu and Stracker, Travis H. and Groth, Anja}},
issn = {{2375-2548}},
language = {{eng}},
month = {{08}},
number = {{8}},
publisher = {{American Association for the Advancement of Science (AAAS)}},
series = {{Science Advances}},
title = {{Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors}},
url = {{http://dx.doi.org/10.1126/sciadv.aat4985}},
doi = {{10.1126/sciadv.aat4985}},
volume = {{4}},
year = {{2018}},
}