Why structure and chain length matter: on the biological significance underlying the structural heterogeneity of poly(ADP-ribose)

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a multifaceted post-translational modification, carried out by poly(ADP-ribosyl)transferases (poly-ARTs, PARPs), which play essential roles in (patho-) physiology, as well as cancer therapy. Using NAD+ as a substrate, acceptors, such as proteins and nucleic acids, can be modified with either single ADP-ribose units or polymers, varying considerably in length and branching. Recently, the importance of PAR structural heterogeneity with regards to chain length and branching came into focus. Here, we provide a concise overview on the current knowledge of the biochemical and physiological significance of such differently structured PAR. There is increasing evidence revealing that PAR’s structural diversity influences the binding characteristics of its readers, PAR catabolism, and the dynamics of biomolecular condensates. Thereby, it shapes various cellular processes, such as DNA damage response and cell cycle regulation. Contrary to the knowledge on the consequences of PAR’s structural diversity, insight into its determinants is just emerging, pointing to specific roles of different PARP members and accessory factors. In the future, it will be interesting to study the interplay with other post-translational modifications, the contribution of natural PARP variants, and the regulatory role of accessory molecules. This has the exciting potential for new therapeutic approaches, with the targeted modulation and tuning of PARPs’ enzymatic functions, rather than their complete inhibition, as a central premise.

Mechanistic insights into the enhancement or inhibition of phase separation by polyubiquitin chains of different lengths or linkages

“…Through promoting or inhibiting LLPS, polyUb chains could be potent modulators of signaling outcomes in the cell, akin to PARylation, another PTM that regulates LLPS via length and branching (Reber and Mangerich, 2021). For example, both K11- and K48-linked chains are linked to proteasomal degradation pathways, with a branched K11/K48 chain binding more tightly to the proteasome (Boughton et al, 2019).…”

Fueling genome maintenance: On the versatile roles of NAD+ in preserving DNA integrity

“…Diphtheria toxin–like ADP-ribosyltransferases (ARTDs; also called poly-ADP-ribose polymerases [PARPs]) come in three flavors: (i) without any known enzymatic activity, (ii) as mono-ARTs catalyzing mono-ADP-ribosylation, or (iii) as poly-ARTs, catalyzing the attachment of numerous ADPR moieties, forming poly-ADP-ribose (PAR) chains in the process called poly(ADP-ribosyl)ation (PARylation). ADP-ribosylation is a post-translational modification that serves multiple cellular functions, such as signal transduction, energy metabolism, intracellular trafficking, or cell death ( 49 , 50 , 51 ). Yet, one of its major roles is the maintenance of nuclear homeostasis, regulation of DNA repair mechanism, chromatin remodeling, and transcription ( 52 ).…”

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

“…Conjugation of PAR to substrates can occur as a monomer (i.e., MARylation) or a complex polymer exceeding 60 units in length. [ 94,95 ] PAR chains also occur in both branched and linear forms, which can further direct effector binding and function (Figure 2B). [ 96 ] This diversity in PAR chain length and conformation suggests that functional codes may exist for PAR, akin to PTMs on histones that comprise “the histone code.” Our work has revealed that the KDM5A CC domain preferentially binds to midsized and long PAR chains (≥ 27‐mer) with an affinity comparable to established PAR binding domains.…”