PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

Abstract

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

“…ADPRE consists of the PARP1 homology protein, which is also produced by the catalytic activity of ADP-ribosyl transferase reactions [ 19 ]. The PARP family has approximately 17 members; a few of them (PARP1, PARP2, PARP5A, and PARP5B) are synthesized 1–3PAR chains [ 11 ]. Usually, enzymes from this family produce single ADP-ribose units called MARs (mono (ADP-ribosyl)ases) [ 18 , 19 ].…”

“…PARP1 has acceptable therapeutic importance against cancer, as shown in Figure 1 and Figure 2 [ 10 ]. PARP inhibitors have emerged as effective treatments in clinical trials for sporadic TNBC and BRCA -associated cancers [ 11 ]. There are various types of PARP inhibitors under clinical trial such as olaparib, BSI-201, talazoparib, rucaparib veliparib, and niraparib [ 10 , 11 ].…”

“…PARP inhibitors have emerged as effective treatments in clinical trials for sporadic TNBC and BRCA -associated cancers [ 11 ]. There are various types of PARP inhibitors under clinical trial such as olaparib, BSI-201, talazoparib, rucaparib veliparib, and niraparib [ 10 , 11 ]. Inhibition of the PARP-1 and PARP-2 enzymes is believed to be attained mainly via binding of the NAD+ catalytic domain side chain, extending out of the NAD catalytic site of the PARP inhibitor [ 12 ].…”

“…Inhibition of the PARP-1 and PARP-2 enzymes is believed to be attained mainly via binding of the NAD+ catalytic domain side chain, extending out of the NAD catalytic site of the PARP inhibitor [ 12 ]. It also thought that the PARP enzyme locks on to the site of DNA damage, preventing its usual release from DNA molecules [ 10 , 11 , 12 , 13 , 14 , 15 ]. PARP-1 binds to the damaged site through its zinc-finger domains in the presence of SS (single-stranded)-DNA breaks [ 13 ].…”

ADP-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

“…The dimer partners ADP-ribosylate each other, which may be relevant for the efficient DNA repair of single-strand and double-strand breaks [ 7 , 8 ]. PARP3 binds to PARP1 and activates PARP1 by MARylation even in the absence of DNA damage [ 9 , 10 , 11 ].…”