Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-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 the one hand, we uncovered a cooperative interplay between PARP1 and UHRF1 in the accumulation of the heterochromatin repressive mark H4K20me3. The absence of PARP1 led to reduced accumulation of H4K20me3 onto pericentric heterochromatin that coincided with abnormally enhanced transcription. The loss of H4K20me3 was rescued by the additional depletion of UHRF1. In contrast, although PARP1 also seemed to facilitate the association of UHRF1 with DNMT1, its absence did not impair the loading of DNMT1 onto heterochromatin or the methylation of pericentric regions, possibly owing to a compensating interaction of DNMT1 with PCNA. On the other hand, we showed that PARP1 controls the UHRF1-mediated ubiquitination of DNMT1 to timely regulate its abundance during S and G2 phase. 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.

The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art.

Poly(ADP-ribose) polymerase (PARP) catalyzed poly(ADP-ribosyl)ation is one of the earliest post-translational modification of proteins detectable at sites of DNA strand interruptions. The considerable recent progress in the science of PARP in the last decade and the discovery of a PARP superfamily (17 members) has introduced this modification as a key mechanism regulating a wide variety of cellular processes including among others transcription, regulation of chromatin dynamics, telomere homeostasis, differentiation and cell death. However, the most extensive studied and probably the best characterized role is in DNA repair where it plays pivotal roles in the processing and resolution of the damaged DNA. Although much of the focus has been on PARP1 in DNA repair, recent advances highlight the emergence of other DNA-dependent PARPs (i.e. PARP2, PARP3 and possibly Tankyrase) in this process. Here we will summarize the recent insights into the molecular functions of these PARPs in different DNA repair pathways in which they emerge as specific actors. Furthermore, the DNA repair functions of PARP1 have stimulated another area of intense research in the field with the development of potent and selective PARP1 inhibitors to promote genome instability and cell death in tumor cells. Their current use in clinical trials have demonstrated potentiation of antitumoral drugs and cytotoxicity in repair deficient tumor cells.