New directions in poly(ADP‐ribose) polymerase biology

Abstract

Poly(ADP-ribose) polymerases (PARPs) regulate the function of target proteins by modifying them with ADP-ribose, a large and unique posttranslational modification. Humans express 17 PARPs; however, historically, much of the focus has been on PARP1 and its function in DNA damage repair. Recent work has uncovered an amazing diversity of function for these enzymes including the regulation of fundamental physiological processes in the cell and at the organismal level, as well as new roles in regulating cellular stress responses. In this review, we discuss recent advancements in our understanding of this important protein family, and technological developments that have been critical for moving the field forward. Finally, we discuss new directions that we feel are important areas of further scientific exploration.

Insights into the biogenesis, function, and regulation of ADP-ribosylation

“…These domains play important roles in targeting the ARTs to their substrates and to specific cellular locations, and in some cases are able to sense specific cellular conditions such as DNA damage 19,33,34 . Although domains play important roles in ART function the key feature used to categorize the ART superfamily is the presence of certain catalytic amino acids within the ART fold 1,35 .…”

“…The eukaryotic ART targeting domains and signals sequences include nuclear localization signals, ER targeting sequences, DNA and RNA binding domains, protein–protein interaction domains, ubiquitin binding domains, and even ADPr binding domains, to list a few 34 . These protein domains target the PARPs to all internal cellular compartments, including the nucleus, cytoplasm, endoplasmic reticulum, and multiple membrane compartments 33 .…”

“…In addition, PARPs play vital roles in regulating cellular stress responses related to the quality control of DNA, RNA and protein—specifically, the DNA damage response, the cytoplasmic stress response, and the unfolded protein response, respectively 12,19,21,46 . PARPs also play roles in the general, nonstress, nondefense pathways in cells by modulating gene expression, telomere length, transcriptional regulation, translation, mRNA stability, cell signaling, cell division and cell motility 17,20,21,33,34,47–49 . Furthermore, they also play important roles in regulating protein stability by targeting proteins for ubiquitylation by directly PARylating them 13–16 .…”

“…This suggests that protein binding was an early step in the evolution of ADPr function in ARTs and that, in addition to modifying the function of protein targets, ADP-ribosylation functions as an important signaling molecule. Collectively, ADPr binding domains are found in over 800 proteins, demonstrating the importance of MAR and PAR binding to eukaryotic life 34 .…”

At the Interface of Three Nucleic Acids: The Role of RNA-Binding Proteins and Poly(ADP-ribose) in DNA Repair

“…The human PARP family includes 17 members with similar catalytic domains [138]. Only four members are capable of catalyzing PAR synthesis: PARP1, PARP2, and two tankirases [138, 139]. PARP1 and PARP2 act as guardians of genome integrity [140].…”