Progress and outlook in studying the substrate specificities of PARPs and related enzymes

FEBS J. 2021 Apr;288(7):2131-2142. doi: 10.1111/febs.15518. Epub 2020 Aug 29.

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.

Keywords: ADP-ribosylation; DNA repair; HPF1; PARP; PARP1; PARP9; enzymatic catalysis; poly(ADP-ribosylation); post-translational modification; specificity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / genetics
  • Carrier Proteins / genetics
  • Catalysis
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • DNA / genetics*
  • Humans
  • Nuclear Proteins / genetics
  • Poly (ADP-Ribose) Polymerase-1 / chemistry
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly(ADP-ribose) Polymerases / chemistry
  • Poly(ADP-ribose) Polymerases / genetics*
  • RNA Caps / genetics
  • Substrate Specificity / genetics

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • HPF1 protein, human
  • Nuclear Proteins
  • RNA Caps
  • DNA
  • ADP Ribose Transferases
  • PARP2 protein, human
  • PARP3 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases