DNA repair and anti-cancer mechanisms in the long-lived bowhead whale.

At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox.

PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation.

Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it remains unclear how exactly PARP1 and PARylation contribute to the formation and organization of DNA repair condensates.

Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection.

ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins.

Cation-induced intramolecular coil-to-globule transition in poly(ADP-ribose).

Poly(ADP-ribose) (PAR), a non-canonical nucleic acid, is essential for DNA/RNA metabolism and protein condensation, and its dysregulation is linked to cancer and neurodegeneration. However, key structural insights into PAR's functions remain largely uncharacterized, hindered by the challenges in synthesizing and characterizing PAR, which are attributed to its length heterogeneity. A central issue is how PAR, comprised solely of ADP-ribose units, attains specificity in its binding and condensing proteins based on chain length.

A ligand discovery toolbox for the WWE domain family of human E3 ligases.

The WWE domain is a relatively under-researched domain found in twelve human proteins and characterized by a conserved tryptophan-tryptophan-glutamate (WWE) sequence motif. Six of these WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. The general recognition of poly-ADP-ribosylated substrates by WWE domains suggests a potential avenue for development of Proteolysis-Targeting Chimeras (PROTACs).

Risk of Seizure Aggravation after COVID-19 Vaccinations in Patients with Epilepsy.

Although Coronavirus disease 2019 (COVID-19) vaccinations are generally recommended for persons with epilepsy (PwE), a significant vaccination gap remains due to patient concerns over the risk of post-vaccination seizure aggravation (PVSA). In this single-centre, retrospective cohort study, we aimed to determine the early (7-day) and delayed (30-day) risk of PVSA, and to identify clinical predictors of PVSA among PwE. Adult epilepsy patients aged ≥18 years without a history of COVID-19 infection were recruited from a specialty epilepsy clinic in early 2022.

Proteogenomic Reprogramming to a Functional Human Totipotent Stem Cell State via a PARP-DUX4 Regulatory Axis.

PARP1 (ARTD1) and Tankyrases (TNKS1/TNKS2; PARP5a/5b) are poly-ADP-ribose polymerases (PARPs) with catalytic and non-catalytic functions that regulate both the genome and proteome during zygotic genome activation (ZGA), totipotent, and pluripotent embryonic stages. Here, we show that primed, conventional human pluripotent stem cells (hPSC) cultured continuously under non-specific TNKS1/TNKS2/PARP1-inhibited chemical naive reversion conditions underwent epigenetic reprogramming to clonal blastomere-like stem cells. TIRN stem cells concurrently expressed hundreds of gene targets of the ZGA-priming pioneer factor DUX4, as well as a panoply of four-cell (4C)-specific (e.

Diagnostic Challenges of Lyme Neuroborreliosis in Inpatient Neurology: A Case Series.

Lyme disease is a multisystem disorder transmitted through the Ixodes tick and is most commonly diagnosed in northeastern and mid-Atlantic states, Wisconsin, and Minnesota, though its disease borders are expanding in the setting of climate change. Approximately 10%-15% of untreated Lyme disease cases will develop neurologic manifestations of Lyme neuroborreliosis (LNB). Due to varying presentations, LNB presents diagnostic challenges and is associated with a delay to treatment.

Transcriptome regulation by PARP13 in basal and antiviral states in human cells.

The RNA-binding protein PARP13 is a primary factor in the innate antiviral response, which suppresses translation and drives decay of bound viral and host RNA. PARP13 interacts with many proteins encoded by interferon-stimulated genes (ISG) to activate antiviral pathways including co-translational addition of ISG15, or ISGylation. We performed enhanced crosslinking immunoprecipitation (eCLIP) and RNA-seq in human cells to investigate PARP13's role in transcriptome regulation for both basal and antiviral states.

PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation.

Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it is not understood how PARP1 and PARylation contribute to the formation and organization of DNA repair condensates.

Length-dependent Intramolecular Coil-to-Globule Transition in Poly(ADP-ribose) Induced by Cations.

Poly(ADP-ribose) (PAR), as part of a post-translational modification, serves as a flexible scaffold for noncovalent protein binding. Such binding is influenced by PAR chain length through a mechanism yet to be elucidated. Structural insights have been elusive, partly due to the difficulties associated with synthesizing PAR chains of defined lengths.

PARP10 is Critical for Stress Granule Initiation.

Stress granules (SGs) are cytoplasmic biomolecular condensates enriched with RNA, translation factors, and other proteins. They form in response to stress and are implicated in various diseased states including viral infection, tumorigenesis, and neurodegeneration. Understanding the mechanism of SG assembly, particularly its initiation, offers potential therapeutic avenues.

Molecular tools unveil distinct waves of ADP-ribosylation during DNA repair.

ADP-ribosylation is a complex post-translation modification involved in DNA repair. In a recent publication, Longarini and colleagues measured ADP-ribosylation dynamics with unprecedented specificity, revealing how the monomeric and polymeric forms of ADP-ribosylation regulate the timing of DNA repair events following strand breaks.

Hydrological responses to early-peak rainfall in unsaturated rooted soils.

Vegetation has been commonly used in sponge city to remediate problems related to rainstorm events. Unlike uniform rainfall which has been widely studied, effects of early-peak rainfall on hydrological responses in vegetated soils are unclear. Besides, there is a lack of quantitative method of accurately measuring wetting front (WF).

Switch-like compaction of poly(ADP-ribose) upon cation binding.

Poly(ADP-ribose) (PAR) is a homopolymer of adenosine diphosphate ribose that is added to proteins as a posttranslational modification to regulate numerous cellular processes. PAR also serves as a scaffold for protein binding in macromolecular complexes, including biomolecular condensates. It remains unclear how PAR achieves specific molecular recognition.

PARPs and ADP-ribosylation: Deciphering the complexity with molecular tools.

PARPs catalyze ADP-ribosylation-a post-translational modification that plays crucial roles in biological processes, including DNA repair, transcription, immune regulation, and condensate formation. ADP-ribosylation can be added to a wide range of amino acids with varying lengths and chemical structures, making it a complex and diverse modification. Despite this complexity, significant progress has been made in developing chemical biology methods to analyze ADP-ribosylated molecules and their binding proteins on a proteome-wide scale.

Switch-like Compaction of Poly(ADP-ribose) Upon Cation Binding.

Unlabelled: Poly(ADP-ribose) (PAR) is a homopolymer of adenosine diphosphate ribose that is added to proteins as a post-translational modification to regulate numerous cellular processes. PAR also serves as a scaffold for protein binding in macromolecular complexes, including biomolecular condensates. It remains unclear how PAR achieves specific molecular recognition.

Pro-Viral and Anti-Viral Roles of the RNA-Binding Protein G3BP1.

Viruses depend on host cellular resources to replicate. Interaction between viral and host proteins is essential for the pathogens to ward off immune responses as well as for virus propagation within the infected cells. While different viruses employ unique strategies to interact with diverse sets of host proteins, the multifunctional RNA-binding protein G3BP1 is one of the common targets for many viruses.

Fluorescence-Based Analyses of Poly(ADP-Ribose) Length by Gel Electrophoresis, High-Performance Liquid Chromatography, and Capillary Electrophoresis.

Poly(ADP-ribose) (PAR) is a homopolymer made of two or more adenosine diphosphate ribose (ADP-ribose) units. The polymer is usually conjugated to protein as a posttranslational modification playing key roles in cellular processes, such as DNA repair, RNA metabolism, and biomolecular condensate formation. Emergent data revealed that PAR length is highly regulated and determines the selection of and affinity towards protein binders.

Evaluation of telehealth support in an integrated respiratory clinic.

Supporting self-management is key in improving disease control, with technology increasingly utilised. We hypothesised the addition of telehealth support following assessment in an integrated respiratory clinic could reduce unscheduled healthcare visits in patients with asthma and COPD. Following treatment optimisation, exacerbation-prone participants or those with difficulty in self-management were offered telehealth support.

Crystal structures and functional analysis of the ZnF5-WWE1-WWE2 region of PARP13/ZAP define a distinctive mode of engaging poly(ADP-ribose).

PARP13/ZAP (zinc-finger antiviral protein) acts against multiple viruses by promoting degradation of viral mRNA. PARP13 has four N-terminal zinc (Zn) fingers that bind CG-rich nucleotide sequences, a C-terminal ADP ribosyltransferase fold, and a central region with a fifth Zn finger and tandem WWE domains. The central PARP13 region, ZnF5-WWE1-WWE2, is implicated in binding poly(ADP-ribose); however, there are limited insights into its structure and function.

Poly(ADP-ribose) promotes toxicity of arginine-rich dipeptide repeat proteins.

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in , play a critical role in -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear.