PARP, transcription and chromatin modeling

Abstract

Compaction mode of chromatin and chromatin highly organised structures regulate gene expression. Posttranslational modifications, histone variants and chromatin remodelers modulate the compaction, structure and therefore function of specific regions of chromatin. The generation of poly(ADP-ribose) (PAR) is emerging as one of the key signalling events on sites undergoing chromatin structure modulation. PAR is generated locally in response to stresses. These include genotoxic stress but also differentiation signals, metabolic and hormonal cues. A pictures emerges in which transient PAR formation is essential to orchestrate chromatin remodelling and transcription factors allowing the cell to adapt to alteration in its environment. This review summarizes the diverse factors of ADP-ribosylation in the adaptive regulation of chromatin structure and transcription.

ADP‐ribosylation: new facets of an ancient modification

“…As with other PTMs, ADP‐ribosylation tags are recognized by cellular proteins in a timely manner in order to activate downstream events in the relevant signalling pathways . Therefore, many proteins involved in these pathways possess ADPr‐binding domains within their protein structure . Among the evolutionary widespread ADPr binding domains, the macrodomain has been studied the most extensively.…”

“…Some macrodomains have also evolved enzymatic activity and are capable of hydrolysing ADP‐ribosylation (see below) . As a consequence, macrodomain‐containing proteins are involved in a diverse set of cellular functions, such as chromatin remodelling and DNA‐damage repair, oxidative stress response, metabolic processes and pathogenic mechanisms . In addition to macrodomain, several other widely distributed domains have been described as readers for ADP‐ribosylation, such as the PAR‐binding zinc finger (PBZ) , the WWE (named after three of its conserved residues) , the oligonucleotide/oligosaccharide‐binding (OB) domain and the PAR‐binding motifs (PBM) which is abundant in DNA‐damage repair proteins .…”

“…ADP‐ribosylation in mammals is known to regulate a number of different processes . Best understood is regulation of DNA‐damage repair pathways by PARP1‐3 that are activated upon binding to DNA breaks PARP1 also plays roles in transcription and metabolism . The functions of other PARPs are comparatively much less understood .…”

“…ADP‐ribosylation seems to be particularly prominent in the highest organisms and it is best studied for the poly(ADP‐ribose) polymerase (PARP) superfamily of ART enzymes . Altogether, ADP‐ribosylation is a widespread modification that controls a vast number of cellular processes, including DNA damage repair, transcription, cell‐cycle progression, cell division, unfolded protein response, aging, nitrogen fixation, microbial pathogenicity, cell death and many others . However, our understanding of ADP‐ribosylation is still in its infancy, as can be seen from the current rapid rate of discoveries of previously unknown pathways regulated by ADP‐ribosylation.…”

Reversible mono‐ADP‐ribosylation of DNA breaks

“…In addition, PARPs also catalyse ADP‐ribosylation of many effector proteins such as histones, chromatin remodellers, DNA repair factors such as Ku70/80, p53 . DNA damage‐induced PARylation of histones causes decompaction of chromatin structure . PARylation at the DNA damage site also acts as scaffolding platform for the recruitment of further DNA damage response effectors, such as XRCC1, APLF, ALC1 and Chk1 .…”