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Tousled-like Kinases Stabilize Replication Forks and Show Synthetic Lethality with Checkpoint and PARP Inhibitors

Overview
Journal Sci Adv
Specialties Biology
Science
Date 2018 Aug 14
PMID 30101194
Citations 28
Authors
Affiliations
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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 G. 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 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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References
1.
Clement C, Vassias I, Ray-Gallet D, Almouzni G . Functional Characterization of Histone Chaperones Using SNAP-Tag-Based Imaging to Assess De Novo Histone Deposition. Methods Enzymol. 2016; 573:97-117. DOI: 10.1016/bs.mie.2016.04.004. View

2.
Min W, Bruhn C, Grigaravicius P, Zhou Z, Li F, Kruger A . Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation. Nat Commun. 2013; 4:2993. DOI: 10.1038/ncomms3993. View

3.
Hoek M, Stillman B . Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo. Proc Natl Acad Sci U S A. 2003; 100(21):12183-8. PMC: 218733. DOI: 10.1073/pnas.1635158100. View

4.
Krause D, Jonnalagadda J, Gatei M, Sillje H, Zhou B, Nigg E . Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene. 2003; 22(38):5927-37. DOI: 10.1038/sj.onc.1206691. View

5.
Toledo L, Altmeyer M, Rask M, Lukas C, Larsen D, Povlsen L . ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013; 155(5):1088-103. DOI: 10.1016/j.cell.2013.10.043. View