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

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.

MUC1-C Integrates Chromatin Remodeling and PARP1 Activity in the DNA Damage Response of Triple-Negative Breast Cancer Cells

“…PARP1 plays multiple roles in DNA repair, including the modulation of chromatin structure and repair of DSBs by recruitment of BMI1 and EZH2 to sites of DNA damage (12,28,30,32,33). As reported for BMI1 and EZH2, MUC1-C was also detectable in nuclear complexes with PARP1 ( Fig.…”

“…MUC1-C also plays a role in regulating EZH2 (29), which induces H3K27 trimethylation (H3K27me3) and has been linked to the DDR (30). In this respect, we found that Fig.…”

“…Moreover, we found that this association is increased by DNA damage and is not dependent on PARP1 activity. The formation of MUC1-C/ PARP1 complexes could be mediated by EZH2, the activity of which is inhibited by PARP1-directed PARylation (30,53). By contrast, MUC1-C activates EZH2 (29), indicating that MUC1-C and PARP1 may play counteracting roles in the regulation of H3K27me3 levels.…”

PARylation During Transcription: Insights into the Fine-Tuning Mechanism and Regulation

“…Interestingly, enhancer of zeste homolog 2 (EZH2), belonging to the polycomb repressive complex 2 (PRC2) and associated with transcription repression (H3K27me3 formation), is recruited depending on the enzymatic activity of PARP1 ( Figure 4C) [44,47]. Recent findings have indicated that PARP1 inhibits the histone methyltransferase activity of EZH2, thus resulting in a more relaxed chromatin structure at the damaged regions [117,118]. Nevertheless, these opposing observations may arise from different kinds of DNA damage source, inducing different repair pathways or even from diverse phases of the repair process.…”

A three layered histone epigenetics in breast cancer metastasis

“…PARP9 has been reported to enhance doxorubicin resistance via H4 ubiquitination and protecting the cell from further DNA damage [170]. EZH2 (Enhancer of Zeste 2), component of polycomb repressive complex (PRC2) is known for mediating breast cancer progression and metastasis via H3K27 tri-methylation [171]. PARylation of histone H3 decreases the affinity of EZH2 for histone H3 and as a result global reduction in H3K27 methylation is observed [171].…”