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.
Highlights
The enzyme Poly(ADP-ribose) polymerase I (PARP1) is a well-known player in the DNA damage response [1]
Since Poly(ADP-ribose) polymerase 1 (PARP1) PARylates proteins important in the DNA damage response, and because it has been reported that EZH2 plays a role in DNA repair, we hypothesized that in response to DNA damage, PARP1 modifies EZH2
In this study we investigated the role of PARP1 in regulating EZH2 functions in the context of DNA damage
Summary
The enzyme Poly(ADP-ribose) polymerase I (PARP1) is a well-known player in the DNA damage response [1]. PARP family members alter the function of target proteins by adding negatively charged polymers of ADP-ribose in an enzymatic reaction referred to as PARylation [2, 3]. PARP1 PARylates a number of target proteins involved in DNA damage repair, including PARP1 itself, transcription factors [4], chromatin www.impactjournals.com/oncotarget modifiers [5, 6] and histones H1, H2 and H3 [7, 8]. The presence of long, negatively charged ADP-ribose polymers significantly alters target proteins. PARP1 activation is required for the DNA damage response, exactly why, and what activated PARP1 is necessary for, are not fully understood. The strict requirement for activated PARP1 in the DNA damage response suggests that additional PARP1 targets, especially targets intimately linked to the DNA damage response, remain to be identified
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