Lectures and seminars OnkPat Extra Seminar: The positively charged residues along the intrinsically disordered automodification domain of PARP1 control stable association with DNA breaks and ADP-ribosylation activity

Host: Maurice Michel, Department of Oncology-Pathology

Abstract

Although intrinsically disordered regions are ubiquitous in eukaryotic proteins, their functions are often neglected. This has been the case for PARP1, a multi-domain protein that is a crucial first responder to DNA damage and a clinical cancer drug target, in addition to being one of the best studied allosteric enzyme systems. While the functions of its individual conserved folded domains are increasingly well-understood, its intrinsically disordered automodification domain (AD) has not been explored beyond its role as a site of PARP1-catalysed auto-ADP-ribosylation. Here, we revisit key aspects of PARP1 function, demonstrating that the positively-charged residues on AD make a crucial contribution to biologically and clinically relevant functions of PARP1 including its association with both undamaged DNA and DNA breaks, as well as its catalytic activation. In contrast, the function of positively-charged residues on the neighbouring folded BRCT domain is limited to undamaged DNA binding. This finding provides a biochemical basis for the detrapping effect of AD ADP-ribosylation, as this modification counteracts the crucial positive charges. Together, these data demonstrate the key role of specific chemical ‘grammar’, here positive charges, of an intrinsically disordered region in the function of a model allosteric enzyme and clinical cancer drug target.

Bio

2002: MSc in Optics, University Paris Sud

2006: PhD in Biophysics, University Pierre et Marie Curie, Analysis of secretory granule movements in the vicinity of the plasma membrane

2006-2010: Post-doc in the Ellenberg lab at EMBL, Heidelberg, Impact of the chromatin architecture on protein motion in the nucleus

2011: Associate-professor in biochemistry and cell biology, University of Rennes

2022: Professor in Biophysics, University of Rennes