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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.

Original publication

DOI

10.1111/febs.15518

Type

Journal article

Journal

FEBS J

Publication Date

04/2021

Volume

288

Pages

2131 - 2142

Keywords

ADP-ribosylation, DNA repair, HPF1, PARP, PARP1, PARP9, enzymatic catalysis, poly(ADP-ribosylation), post-translational modification, specificity, ADP Ribose Transferases, Carrier Proteins, Catalysis, Cell Cycle Proteins, DNA, Humans, Nuclear Proteins, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, RNA Caps, Substrate Specificity