Multiple Roles for Mono- and Poly(ADP-Ribose) in Regulating Stress Responses

Abstract

While stress-induced synthesis of mono ADP-ribose (mADPr) and poly ADP-ribose (pADPr) conjugates by PARP enzymes has been studied extensively, the removal and degradation of pADPr, and the fate of ADPr metabolites has received less attention. The observations that stressinduced pADPr undergoes rapid turnover and deficiencies in ADPr degradation phenocopy loss of pADPr synthesis suggest that ADPr degradation is fundamentally important to the cellular stress response. Recent work has identified several distinct families of pADPr hydrolyases that can degrade pADPr to release pADPr or mADPr into the cytoplasm. Further, many stress response proteins contain ADPr binding domains that can interact with these metabolites. Here, we will discuss how pADPr metabolites generated during pADPr degradation can function as signaling intermediates in processes such as inflammation, apoptosis and DNA damage responses. These studies highlight that the full cycle of ADPr metabolism, including both synthesis and degradation, is necessary for responses to genotoxic stress. Conjugation of ADP-ribose (ADPr) to proteins plays a critical signaling function in gene transcription, chromatin organization and stress responses. Poly-ADPr polymerase (PARP1) was originally thought responsible for producing all cellular ADPr (1). However, PARP1 is one of 18 human enzymes (also known as diphtheria toxin-type ADP-ribose transferases (ARTDs, See Glossary), reviewed in (2)), which can ADP ribosylate proteins. Further, families of ADPr hydrolases which cleave pADPr chains, protein-ADPr bonds or which remove the terminal mADPr from pADPr chains have been identified. In addition, multiple ADPr binding domains have been described. There are therefore both writers and erasers of ADPr as well as protein modules that can read mADPr and pADPr. Protein-mADPr, pADPr polymers (both protein-linked and soluble) and free mADPr may therefore represent distinct functional signaling effectors in the cell.

The role of poly(ADP-ribose) polymerase inhibitors in the treatment of cancer and methods to overcome resistance: a review

“…Eighteen PARPs have been described and can be broadly categorized into 3 groups by catalytic activity [9]. PARP1, PARP2, PARP5a and PARP5b catalyze the formation of branching pADPr chains up to 200 units long.…”

“…PARP9, PARP13, and PARP18 either lack activity or have been uncharacterized. The remaining PARPs only catalyze the addition of a single ADP-ribose unit [mono(ADP-ribose), or mADPr] [9,10].…”

Monitoring global changes in chromatin compaction states upon localized DNA damage with tools of fluorescence anisotropy

“…PARP1 is known to be transiently enhanced at sites of damage in response to irradiation-induced DSBs ( Chou et al. , 2010 ; Qi et al. , 2019 ), while PCNA, being the DNA clamp, would be required for the processivity of the DNA polymerase in the final steps of repair ( Moldovan et al.…”

PARP1 and Poly(ADP-ribosyl)ation Signaling during Autophagy in Response to Nutrient Deprivation

“…Several data suggest that PARP1-induced loss of ATP requires PARG activity. Under specific scenarios of PARP1 hyperactivation, PARG-dependent production of the single unit of ADPr can exit from the nucleus and interfere with ATP production in mitochondria, promoting nonenzymatic ADP-ribosylation of cell death proteins and metabolic cofactors [4, 6, 7].…”

“…As fundamentally important as PAR synthesis in stress response is the following degradation of the ADP-ribose chains by families of ADP-ribose hydrolases. While some enzymes preferentially degrade Poly(ADP-ribose) chains (the macrodomain containing PARG endowed with exo- and endoglycohydrolase activities or ARH3), the removal of the last protein ADP-ribose bond is mediated by a panel of recently identified enzymes including ARH3, TARG1, macroD1, macroD2, NUDT16, or ENPP1 [4].…”