Abstract
Despite decades of research on ADP-ribosyltransferases (ARTs) from the poly(ADP-ribose) polymerase (PARP) family, one key aspect of these enzymes - their substrate specificity - has remained unclear. Here, we briefly discuss the history of this area and, more extensively, the recent breakthroughs, including the identification of protein serine residues as a major substrate of PARP1 and PARP2 in human cells and of cysteine and tyrosine as potential targets of specific PARPs. On the molecular level, the modification of serine residues requires a composite active site formed by PARP1 or PARP2 together with a specificity-determining factor, HPF1; this represents a new paradigm not only for PARPs but generally for post-translational modification (PTM) catalysis. Additionally, we discuss the identification of DNA as a substrate of PARP1, PARP2 and PARP3, and some bacterial ARTs and the discovery of noncanonical RNA capping by several PARP family members. Together, these recent findings shed new light on PARP-mediated catalysis and caution to 'expect the unexpected' when it comes to further potential substrates.
Highlights
adenine dinucleotide (ADP)-ribosylation is a widespread protein post-translational modification (PTM) that involves the enzymatic transfer of the ADP-ribosyl moiety from b-NAD+ to a protein amino acid residue [1] (Fig. 1)
For these reasons, knowing poly(ADP-ribose) polymerase (PARP) substrates and the exact modification sites is crucial for understanding ADP-ribose-dependent regulation (Fig. 2). This is as important for poly(ADP-ribose) polymerase 1 (PARP1) as it is for other PARP family members, whose emerging specialised functions [18] might depend on distinct specificities
While it is possible that deltex 3-like (DTX3L) complements PARP9 active site in a manner not dissimilar to the histone PARylation factor 1 (HPF1)-PARP1/2 scenario, in the light of the above considerations we would expect that the modification of the C-terminal carboxyl group, like that of glutamate or aspartate residues, does not require dedicated catalytic residues and instead proceeds in a substrate-assisted manner
Summary
ADP-ribosylation can be catalysed by more diverged cholera toxin-like ARTs (ARTCs) and unrelated sirtuins [9]. Like most other PTMs, ADP-ribosylation is reversible; in human cells, it can be removed by numerous ‘eraser’ enzymes that possess ADP-ribosylglycohydrolase activity [10,11]. Chain formation has been observed for PARP2 and PARP5a/ b (tankyrase) [9]. PAR chains were discovered even prior to their covalent attachment to proteins [13,14] and have attracted a lot of attention. Detached PAR chains have been implicated in triggering a specific form of cell death referred to as parthanatos [17]
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