Abstract
Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD+ as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.
Highlights
ADP-ribosyl transferases, known as poly(ADPribose) polymerases (PARPs), are specific enzymes that transfer the ADP-ribose moiety from b-nicotinamide adenine dinucleotide (NAD+) to a target macromolecule, mainly proteins
In addition to the domains involved in DNA-break recognition and catalytic activation, PARP1 contains a BRCT-like (BRCA1 C-terminus) domain where most of the auto-modification sites have been identified (Altmeyer et al, 2009; Tao et al, 2009) and which is implicated in mediating protein-protein interactions (Liu et al, 2011; Noren Hooten et al, 2011; Hsu et al, 2019)
In the case of DNA single-strand break repair (SSBR), PARP1 and PARP2-dependent ADP-ribosylation leads to the recruitment of the central scaffolding protein XRCC1, which contains a PAR-binding BRCT domain (Caldecott, 2008; Breslin et al, 2015; Polo et al, 2019)
Summary
ADP-ribosyl transferases, known as poly(ADPribose) polymerases (PARPs), are specific enzymes that transfer the ADP-ribose moiety from b-nicotinamide adenine dinucleotide (NAD+) to a target macromolecule, mainly proteins. In addition to the domains involved in DNA-break recognition and catalytic activation, PARP1 contains a BRCT-like (BRCA1 C-terminus) domain where most of the auto-modification sites have been identified (Altmeyer et al, 2009; Tao et al, 2009) and which is implicated in mediating protein-protein interactions (Liu et al, 2011; Noren Hooten et al, 2011; Hsu et al, 2019)
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