On November 16, 2021, Clarivate Analytics announced the list of “Highly Cited Researchers 2021". Prof. Ted M. Dawson, our Honorary Editor-in-Chief, is on the list. This week, we would like to share several latest articles from Prof. Ted M. Dawson.
Title: USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing
Authors: Jae Jin Kim, Seo Yun Lee, Yiseul Hwang, Soyeon Kim, Jee Min Chung, Sangwook Park, Junghyun Yoon, Hansol Yun, Jae-Hoon Ji, Sunyoung Chae, Hyeseong Cho, Chan Gil Kim, Ted M Dawson, Hongtae Kim, Valina L Dawson, Ho Chul Kang
Type: Article Navigation of Nucleic Acids Research
Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR.
Access this article: https://doi.org/10.1093/nar/gkab892
Title: Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation
Authors: Volkan Yazar, Sung-Ung Kang, Shinwon Ha, Valina L. Dawson, Ted M. Dawson
Type: Article of Scientific Reports
The transcriptional repressor called parkin interacting substrate (PARIS; ZNF746) was initially identified as a novel co-substrate of parkin and PINK1 that leads to Parkinson’s disease (PD) by disrupting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma (PPARγ) coactivator -1α (PGC-1α) suppression. Since its initial discovery, growing evidence has linked PARIS to defective mitochondrial biogenesis observed in PD pathogenesis. Yet, dopaminergic (DA) neuron-specific mechanistic underpinnings and genome-wide PARIS binding landscape has not been explored. We employed conditional translating ribosome affinity purification (TRAP) followed by RNA sequencing (TRAP-seq) for transcriptome profiling of DA neurons in transgenic Drosophila lines expressing human PARIS wild type (WT) or mutant (C571A). We also generated genome-wide maps of PARIS occupancy using ChIP-seq in human SH-SY5Y cells. The results demonstrated that PPARγ functions as a master regulator of PARIS-induced molecular changes at the transcriptome level, confirming that PARIS acts primarily on PGC-1α to lead to neurodegeneration in PD. Moreover, we identified that PARIS actively modulates expression of PPARγ target genes by physically binding to the promoter regions. Together, our work revealed how PARIS drives adverse effects on modulation of PPAR-γ associated gene clusters in DA neurons.
Access this article: https://doi.org/10.1038/s41598-021-00858-7
Title: ADP-ribosyltransferases, an update on function and nomenclature
Authors: Bernhard Lüscher, Ivan Ahel, Matthias Altmeyer, Alan Ashworth, Peter Bai, Paul Chang, Michael Cohen, Daniela Corda, Françoise Dantzer, Matthew D. Daugherty, Ted M. Dawson, Valina L. Dawson, Sebastian Deindl, Anthony R. Fehr, Karla L. H. Feijs, Dmitri V. Filippov, Jean-Philippe Gagné, Giovanna Grimaldi, Sebastian Guettler, Nicolas C. Hoch, Michael O. Hottiger, Patricia Korn, W. Lee Kraus, Andreas Ladurner, Lari Lehtiö, Anthony K. L. Leung, Christopher J. Lord, Aswin Mangerich, Ivan Matic, Jason Matthews, George-Lucian Moldovan, Joel Moss, Gioacchino Natoli, Michael L. Nielsen, Mario Niepel, Friedrich Nolte, John Pascal, Bryce M. Paschal, Krzysztof Pawłowski, Guy G. Poirier, Susan Smith, Gyula Timinszky, Zhao-Qi Wang, José Yélamos, Xiaochun Yu, Roko Zaja, Mathias Ziegler
Type: Viewpoint of The FEBS Journal
ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.
Access this article: https://doi.org/10.1111/febs.16142
Title: Targeting Parthanatos in Ischemic Stroke
Authors: Raymond C. Koehler, Valina L. Dawson, Ted M. Dawson
Type: Review Article of Front. Neurol.
Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4–6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.
Access this article: https://doi.org/10.3389/fneur.2021.662034