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J Biol Chem. 2014 Jun 6;289(23):16223-38. doi: 10.1074/jbc.M113.527424. Epub 2014 Apr 29.

Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions.

Author information

1
From the Poly(ADP-ribosyl)ation and Genome Integrity Group, Equipe Labellisée Ligue Nationale Contre le Cancer, Laboratoire d'Excellence Medalis, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Boulevard Sebastien Brant, BP10413, 67412 Illkirch, France.
2
the Department of Biology II, Center for Integrated Protein Science Munich, Ludwig Maximilians University Munich, 82152 Planegg-Martinsried, Germany, and.
3
the Department of Structural and Functional Biology, University of Insubria, Via Alberto da Giussano 12, 21052 Busto Arsizio, Italy.
4
From the Poly(ADP-ribosyl)ation and Genome Integrity Group, Equipe Labellisée Ligue Nationale Contre le Cancer, Laboratoire d'Excellence Medalis, Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg, UMR7242, Centre Nationale de la Recherche Scientifique/Université de Strasbourg, Boulevard Sebastien Brant, BP10413, 67412 Illkirch, France, francoise.dantzer@unistra.fr.

Abstract

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.

KEYWORDS:

DNA Methylation; Heterochromatin; Histone Modification; Poly(ADP-ribose) Polymerase; Post-translational Modification (PTM); Transcription; UHRF1; Ubiquitination

PMID:
24782312
PMCID:
PMC4047392
DOI:
10.1074/jbc.M113.527424
[Indexed for MEDLINE]
Free PMC Article
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