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

Research output: Contribution to journalJournal articlepeer-review

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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, 2018, p. 1-14.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Lee, S-B, Segura-Bayona, S, Villamor-Payà, M, Saredi, G, Todd, MAM, Attolini, CS-O, Chang, T-Y, 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, pp. 1-14. https://doi.org/10.1126/sciadv.aat4985

APA

Lee, S-B., Segura-Bayona, S., Villamor-Payà, M., Saredi, G., Todd, M. A. M., Attolini, C. S-O., Chang, T-Y., Stracker, T. H., & Groth, A. (2018). Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Science Advances, 4(8), 1-14. [eaat4985]. https://doi.org/10.1126/sciadv.aat4985

Vancouver

Lee S-B, Segura-Bayona S, Villamor-Payà M, Saredi G, Todd MAM, Attolini CS-O et al. Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Science Advances. 2018;4(8):1-14. eaat4985. https://doi.org/10.1126/sciadv.aat4985

Author

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. pp. 1-14.

Bibtex

@article{962624f9fad740e289568601237f0ced,
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 = "Sung-Bau Lee and Sandra Segura-Bayona and Marina Villamor-Pay{\`a} and Giulia Saredi and Todd, {Matthew A M} and Attolini, {Camille Stephan-Otto} and Ting-Yu Chang and Stracker, {Travis H} and Anja Groth",
year = "2018",
doi = "10.1126/sciadv.aat4985",
language = "English",
volume = "4",
pages = "1--14",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "8",

}

RIS

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

Y1 - 2018

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.

U2 - 10.1126/sciadv.aat4985

DO - 10.1126/sciadv.aat4985

M3 - Journal article

C2 - 30101194

VL - 4

SP - 1

EP - 14

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 8

M1 - eaat4985

ER -

ID: 203894911