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Leuk Res. 2016 Jun;45:14-23. doi: 10.1016/j.leukres.2016.03.007. Epub 2016 Mar 30.

Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin.

Author information

1
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
2
The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, United States.
3
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States.
4
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address: frassool@som.umaryland.edu.

Abstract

Histone deacetylase inhibitors (HDACi) induce acetylation of histone and non-histone proteins, and modulate the acetylation of proteins involved in DNA double-strand break (DSB) repair. Non-homologous end-joining (NHEJ) is one of the main pathways for repairing DSBs. Decreased NHEJ activity has been reported with HDACi treatment. However, mechanisms through which these effects are regulated in the context of chromatin are unclear. We show that pan-HDACi, trichostatin A (TSA), causes differential acetylation of DNA repair factors Ku70/Ku80 and poly ADP-ribose polymerase-1 (PARP1), and impairs NHEJ. Repair effects are reversed by treatments with p300/CBP inhibitor C646, with significantly decreased acetylation of PARP1. In keeping with these findings, TSA treatment significantly increases PARP1 binding to DSBs in chromatin. Notably, AML patients treated with HDACi entinostat (MS275) in vivo also show increased formation of poly ADP-ribose (PAR) that co-localizes with DSBs. Further, we demonstrate that PARP1 bound to chromatin increases with duration of TSA exposure, resembling PARP "trapping". Knockdown of PARP1 inhibits trapping and mitigates HDACi effects on NHEJ. Finally, combination of HDACi with potent PARP inhibitor talazoparib (BMN673) shows a dose-dependent increase in PARP "trapping", which correlates with increased apoptosis. These results provide a mechanism through which HDACi inhibits deacetylation and increases binding of PARP1 to DSBs, leading to decreased NHEJ and cytotoxicity of leukemia cells.

KEYWORDS:

DSB repair; HDAC; NHEJ; PARP1

PMID:
27064363
PMCID:
PMC5007632
DOI:
10.1016/j.leukres.2016.03.007
[Indexed for MEDLINE]
Free PMC Article

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