Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitine-protein ligase UHRF1 and modulates UHRF1 biological functions.
Poly(ADP-ribose) polymerase 1 (PARP1, also known as ARTD1) is an abundant nuclear enzyme that plays important roles in DNA repair, gene transcription and differentiation through the modulation of chromatin structure and function. In this work we identify a physical and functional poly(ADP-ribose) mediated interaction of PARP1 with the E3 ubiquitin ligase UHRF1 (also known as NP95, ICBP90) that influences two UHRF1-regulated cellular processes. On one hand, we uncover a cooperative interplay between PARP1 and UHRF1 in the accumulation of the heterochromatin repressive mark H4K20me3. The absence of PARP1 leads to reduced accumulation of H4K20me3 onto pericentric heterochromatin that coincides with abnormally enhanced transcription. The loss of H4K20me3 is rescued by the additional depletion of UHRF1. In contrast, although PARP1 also seems to facilitate the association of UHRF1 with DNMT1, its absence does not impair the loading of DNMT1 onto heterochromatin nor the methylation of pericentric regions possibly owing to a compensating interaction of DNMT1 with PCNA. On the other hand, we show that PARP1 controls the UHRF1-mediated ubiquitination of DNMT1 to timely regulate its abundance during S and G2. Together, this report identifies PARP1 as a novel modulator of two UHRF1-regulated heterochromatin-associated events : the accumulation of H4K20me3 and the clearance of DNMT1.