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Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that FAM118A/B processing of NAD involves head-to-tail filament formation and a partnership between the two paralogs.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

Telomeres are endogenous cellular targets of DNA ADP-ribosylation (DNA-ADPr). TARG1-regulated DNA-ADPr is coupled to lagging telomere DNA strand synthesis, and persistent DNA-ADPr, due to TARG1 deficiency, leads to telomere shortening and fragility.

Poly(ADP-ribose) glycohydrolase catabolises poly(ADP-ribose), which is covalently attached to proteins following post-translational modification. In this study, the structure of poly(ADP-ribose) glycohydrolase fromTetrahymena thermophilais reported in complex with the small molecule inhibitor RBPI-3.

Chromatin “breathing” at DNA lesions is controlled by different waves of histone ADP-ribosylation.

Ester-linked modifications are common but difficult to detect. Here, the authors present methods based on ester preservation and a sensitive antibody to reveal DNA damage-induced mono-ADP-ribosylation on aspartate and glutamate. This signal, part of the first wave of PARP1 signaling, is removed by PARG.

PARP inhibitors function by trapping PARP1 protein on DNA breaks, which has cytotoxic consequences to cancer cells. Here the authors identify three serine residues within PARP1 as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance.

Assembly of a catalytic centre formed by HPF1 bound to PARP1 or PARP2 is essential for protein ADP-ribosylation after DNA damage in human cells.

RNF114 is an E3 ligase that can recognize ADP-ribose (ADPr) and ubiquitin with separate domains. Using these domains, Kolvenbach and Palumbieri et al. developed a proteomics approach to map ADP-ribosyl-ubiquitylation sites, revealing that serine ADPr induced by DNA damage is a target for ubiquitylation.

Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational modification modifies another. This Comment highlights its discovery, mechanistic basis and functional consequences, and outlines critical questions for understanding this emerging signaling paradigm.

A novel poly(ADP-ribose)-binding zinc finger (PBZ) motif is identified. This motif is found in several eukaryotic checkpoint and DNA repair proteins, such as CHFR and APLF. Mutations in the PBZ of CHFR affect its function in checkpoint regulation, suggesting that both the poly (ADP-ribosyl)ation of proteins, and the interaction of this modification with other factors, is important for the DNA damage response.

PARG and ARH3 are the main hydrolases to reverse serine poly(ADP-ribosylation) yet their activities in the process differ. Here, the authors synthesise linear and branched poly(ADP-ribose) molecules, perform structure-function analysis and elucidate the mechanistic differences between PARG and ARH3.

Poly-ADP-ribosylation is a post-translational modification that is countered by poly(ADP-ribose) glycohydrolases (PARGs). In this study, the authors present the crystal structure of poly(ADP-ribose) glycohydrolase (PARGs) in complex with a poly(ADP-ribose) substrate, and reveal that poly(ADP-ribose) glycohydrolase (PARGs) enzymes act predominantly as exo- rather than as endo-glycohydrolases.

ADP-ribosylation is regulated by HPF1 and ARH3, but the cellular target spectrum of these enzymes is not fully understood. Here, the authors use quantitative proteomics to define the HPF1- and ARH3-dependent ADP-ribosylome, providing evidence that mono-ADP-ribosylation of serine predominates in cells.

In the DNA damage response, ADP-ribosylation is an essential signaling pathway. Here the authors utilize a multidisciplinary approach to establish its molecular basis in fruit flies and provide evidence for Drosophila’s suitability as model organism.

Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria.

The poly(ADP-ribose) polymerase family of enzymes control many aspects of cellular signalling by covalently modifying proteins with either poly- or mono-(ADP-ribose). Vyas et al.catalogue the catalytic specificity of this family, and reveal that the majority of these enzymes generate only mono(ADP-ribose).

ADP-ribosylation is a post-translational protein modification that regulates numerous cellular pathways. An approach involving histone purification, partial filter-aided digestion and ETD mass spectrometry reveals that serine residues in histone proteins are ADP-ribosylated.

The PARP2–HPF1 histone-modifying complex bridges two nucleosomes to align broken DNA ends for ligation, initiating conformational changes that activate PARP2 and enable DNA damage repair.

The solution structures of the two PAR-binding zinc finger (PBZ) modules from APLF, a human protein putatively involved in DNA damage response, are now presented. Together with binding studies with PAR fragments and mutagenesis, the work sheds light on PAR recognition by PBZ modules.

Aprataxin cleans up unfinished DNA ligation intermediates. By cleaving off an adenylate group at the site of a ligatable nick, aprataxin generates ends that can then be re-ligated. This suggests that neurodegeneration results from the accumulation of these intermediates in post-mitotic neuronal cells.

Histone variant macroH2A1.1 inhibits PARP activity to maintain mitochondrial NAD⁺ pools in muscle cells, thus linking chromatin state to optimal energy metabolism.

The pathogen Legionella pneumophila mediates NAD⁺-dependent ubiquitination pathways upon infection. Here, the authors show the Legionella effector MavL reverses ubiquitin ADP-ribosylation to regulate these pathways. MavL represents a new macrodomain class specific for reversal of arginine ADP-ribosylation with distinct ADP-ribose binding features.

Fragment-based drug discovery employs screening of small polar compounds typically exhibiting low affinity towards protein targets. Here, the authors combine the use of protein-based binding pharmacophores with the theory of protein hotspots to develop a design protocol for fragment libraries, called SpotXplorer, and validate their approach on common and emerging drug targets.

Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of endogenous or exogenous DNA single-strand breaks.

Smith, Zentout et al. investigate the role of HPF1 in DNA repair using live-cell imaging methods and find that HPF1-dependent histone ADP-ribosylation drives early process in DNA repair, including chromatin relaxation and repair factor recruitment.

Deficiencies in aprataxin, which reverses 5′-adenylate DNA adducts, can lead to the neurodegenerative disorder AOA1. Mutagenesis analyses and the crystal structure of the aprataxin ortholog from Schizosaccharomyces pombe in complex with DNA, AMP and Zn²⁺ reveal the mechanisms by which this enzyme processes DNA lesions and maintains genome integrity.