Oncotarget

Research Papers:

Poly(ADP-ribose) Polymerase 1, PARP1, modifies EZH2 and inhibits EZH2 histone methyltransferase activity after DNA damage

Lisa B. Caruso, Kayla A. Martin, Elisabetta Lauretti, Michael Hulse, Micheal Siciliano, Lena N. Lupey-Green, Aaron Abraham, Tomasz Skorski, Italo Tempera _

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Oncotarget. 2018; 9:10585-10605. https://doi.org/10.18632/oncotarget.24291

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Abstract

Lisa B. Caruso1,*, Kayla A. Martin1,4,*, Elisabetta Lauretti2, Michael Hulse1, Micheal Siciliano3, Lena N. Lupey-Green1,5, Aaron Abraham1, Tomasz Skorski1,3 and Italo Tempera1,3

1Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

2Department of Pharmacology, Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

3Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

4Present address: The Wistar Institute, Philadelphia, PA, USA

5Present address: Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, USA

*These authors have contributed equally to this work

Correspondence to:

Italo Tempera, email: tempera@temple.edu

Keywords: PARP1; EZH2; DNA damage; synthetic lethality; cancer therapy

Received: October 06, 2017    Accepted: January 13, 2018    Published: January 24, 2018

ABSTRACT

The enzyme Poly(ADP-ribose) polymerase 1 (PARP1) plays a very important role in the DNA damage response, but its role in numerous aspects is not fully understood. We recently showed that in the absence of DNA damage, PARP1 regulates the expression of the chromatin-modifying enzyme EZH2. Work from other groups has shown that EZH2 participates in the DNA damage response. These combined data suggest that EZH2 could be a target of PARP1 in both untreated and genotoxic agent-treated conditions. In this work we tested the hypothesis that, in response to DNA damage, PARP1 regulates EZH2 activity. Here we report that PARP1 regulates EZH2 activity after DNA damage. In particular, we find that EZH2 is a direct target of PARP1 upon induction of alkylating and UV-induced DNA damage in cells and in vitro. PARylation of EZH2 inhibits EZH2 histone methyltransferase (H3K27me) enzymatic activity. We observed in cells that the induction of PARP1 activity by DNA alkylating agents decreases the association of EZH2 with chromatin, and PARylation of histone H3 reduces EZH2 affinity for its target histone H3. Our findings establish that PARP1 and PARylation are important regulators of EZH2 function and link EZH2-mediated heterochromatin formation, DNA damage and PARylation. These findings may also have clinical implications, as they suggest that inhibitors of EZH2 can improve anti-tumor effects of PARP1 inhibitors in BRCA1/2-deficient cancers.


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