Poly(ADP-ribose) polymerase (PARP) enzymes are broadly involved in the cellular response to DNA damage. PARP-1 is the chief human PARP enzyme involved in the DNA damage response, acting as a first ...responder that detects DNA strand breaks, and contributes to repair pathway choice and the efficiency of repair through modulation of chromatin structure and through interaction with and modification of a multitude of DNA repair factors. This perspective summarizes our knowledge of PARP-1 involvement in DNA repair pathways, and highlights recent structural and functional data regarding the activation of PARP-1 upon detecting DNA damage, and the release and trapping of PARP-1 at sites of DNA damage.
The risk and severity of specific infections are increased during pregnancy due to a combination of physiological and immunological changes. Characterizing the maternal immune system during pregnancy ...is important to understand how the maternal immune system maintains tolerance towards the allogeneic fetus. This may also inform strategies to prevent maternal fatalities due to infections and optimize maternal vaccination to best protect the mother-fetus dyad and the infant after birth. In this review, we describe what is known about the immunological changes that occur during a normal pregnancy.
•First meta-analysis quantitatively summarizing relevant literature on cognitive event-related potentials (ERPs) in ADHD across the lifespan.•ADHD is associated with alterations in neurophysiological ...functioning during cognitive tasks.•On a group level, individuals with ADHD show moderate deviance mainly regarding later cognitive ERPs (P300, CNV, Pe).•These later cognitive ERPs represent a range of potential ADHD biomarkers.•Substantial heterogeneity and medium effect sizes (d < 0.6) limit the use of ERPs for clinical practice on an individual level.
The current meta-analysis summarizes relevant literature on earlier (P100, N100, P200, N200, ERN/Ne) versus later (P300, Pe, CNV) cognitive Event-Related Potential (ERP) differences between children, adolescents, and adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and without ADHD (non-ADHD). Furthermore, the heterogeneity in previous research is addressed by analyzing potentially relevant demographic and methodological moderators (age group, IQ, medication, comorbidity, task, cognitive function, modality, inter-stimulus-interval, number of electrodes). Via database search 52 relevant articles were identified including n = 1576 ADHD and n = 1794 non-ADHD. Using multilevel-models, pooled effect sizes were calculated. For earlier components, individuals with ADHD showed shorter Go-P100-latencies than non-ADHD. For later ERPs, individuals with ADHD showed smaller Cue-P300-amplitudes, longer Go-P300-latencies, smaller NoGo-P300-amplitudes, longer NoGo-P300-latencies, smaller CNV-amplitudes, and smaller Pe-amplitudes. The substantial heterogeneity identified for most of the ERP components could be explained by the demographic and methodological moderators of interest. This meta-analysis identified relevant moderate group differences (−0.32<d<−0.57), mainly regarding later cognitive ERPs. Nevertheless, results are characterized by substantial heterogeneity and the moderate effect sizes (d<0.6) limit the use for clinical application.
Poly(ADP-ribose) polymerase-1 (PARP-1) (ADP, adenosine diphosphate) has a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through a poorly understood ...mechanism. Here, we report the crystal structure of a DNA double-strand break in complex with human PARP-1 domains essential for activation (Zn1, Zn3, WGR-CAT). PARP-1 engages DNA as a monomer, and the interaction with DNA damage organizes PARP-1 domains into a collapsed conformation that can explain the strong preference for automodification. The Zn1, Zn3, and WGR domains collectively bind to DNA, forming a network of interdomain contacts that links the DNA damage interface to the catalytic domain (CAT). The DNA damage-induced conformation of PARP-1 results in structural distortions that destabilize the CAT. Our results suggest that an increase in CAT protein dynamics underlies the DNA-dependent activation mechanism of PARP-1.
Poly(ADP-ribose)polymerase 1 (PARP-1) is a key eukaryotic stress sensor that responds in seconds to DNA single-strand breaks (SSBs), the most frequent genomic damage. A burst of poly(ADP-ribose) ...synthesis initiates DNA damage response, whereas PARP-1 inhibition kills BRCA-deficient tumor cells selectively, providing the first anti-cancer therapy based on synthetic lethality. However, the mechanism underlying PARP-1’s function remained obscure; inherent dynamics of SSBs and PARP-1’s multi-domain architecture hindered structural studies. Here we reveal the structural basis of SSB detection and how multi-domain folding underlies the allosteric switch that determines PARP-1’s signaling response. Two flexibly linked N-terminal zinc fingers recognize the extreme deformability of SSBs and drive co-operative, stepwise self-assembly of remaining PARP-1 domains to control the activity of the C-terminal catalytic domain. Automodifcation in cis explains the subsequent release of monomeric PARP-1 from DNA, allowing repair and replication to proceed. Our results provide a molecular framework for understanding PARP inhibitor action and, more generally, allosteric control of dynamic, multi-domain proteins.
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•We identify the structural basis of DNA single-strand break detection by PARP-1•An NMR/X-ray approach reveals how multi-domain allostery underlies activity switch•The molecular model of PARP-1 assembly couples damage detection to PAR signaling•Automodification in cis releases enzyme so DNA repair and replication can proceed
Eustermann et al. reveal the structural basis for recognition of DNA single-strand breaks by human PARP-1 and how this drives a multi-domain folding cascade to operate the allosteric switch initiating DNA damage signaling. The structural model of PARP-1 on a DNA break helps rationalize inhibitor action.
Poly(ADP-ribose) polymerase-1 (PARP-1) creates the posttranslational modification PAR from substrate NAD+ to regulate multiple cellular processes. DNA breaks sharply elevate PARP-1 catalytic activity ...to mount a cell survival repair response, whereas persistent PARP-1 hyperactivation during severe genotoxic stress is associated with cell death. The mechanism for tight control of the robust catalytic potential of PARP-1 remains unclear. By monitoring PARP-1 dynamics using hydrogen/deuterium exchange-mass spectrometry (HXMS), we unexpectedly find that a specific portion of the helical subdomain (HD) of the catalytic domain rapidly unfolds when PARP-1 encounters a DNA break. Together with biochemical and crystallographic analysis of HD deletion mutants, we show that the HD is an autoinhibitory domain that blocks productive NAD+ binding. Our molecular model explains how PARP-1 DNA damage detection leads to local unfolding of the HD that relieves autoinhibition, and has important implications for the design of PARP inhibitors.
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•HXMS reveals dramatic changes in PARP-1 dynamics upon binding to DNA damage•The HD subdomain locally unfolds when PARP-1 is bound to DNA damage•The HD is an autoinhibitory domain that blocks productive binding to NAD+•X-ray structures of constitutively active PARPs are determined bound to inhibitors
Dawicki-McKenna, Langelier et al. identify the HD autoinhibitory domain in PARP-1 and reveal that DNA break sensing leads to local unfolding of HD, which allows proper active site positioning of NAD+ and leads to a burst in poly(ADP-ribose) production in response to DNA damage.
PARP-1 cleaves NAD
and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA ...damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD
analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD
binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery. Our findings reveal a two-step mechanism to activate and to then stabilize PARP-1 on a DNA break, indicate that PARP-1 allostery influences persistence on DNA damage, and have important implications for PARP inhibitors that engage the NAD
binding site.
The modulation of brain circuits of emotion is a promising pathway to treat borderline personality disorder (BPD). Precise and scalable approaches have yet to be established. Two studies ...investigating the amygdala-related electrical fingerprint (Amyg-EFP) in BPD are presented: one study addressing the deep-brain correlates of Amyg-EFP, and a second study investigating neurofeedback (NF) as a means to improve brain self-regulation.
Study 1 combined electroencephalography (EEG) and simultaneous functional magnetic resonance imaging to investigate the replicability of Amyg-EFP-related brain activation found in the reference dataset (
= 24 healthy subjects, 8 female; re-analysis of published data) in the replication dataset (
= 16 female individuals with BPD). In the replication dataset, we additionally explored how the Amyg-EFP would map to neural circuits defined by the research domain criteria. Study 2 investigated a 10-session Amyg-EFP NF training in parallel to a 12-weeks residential dialectical behavior therapy (DBT) program. Fifteen patients with BPD completed the training,
= 15 matched patients served as DBT-only controls.
Study 1 replicated previous findings and showed significant amygdala blood oxygenation level dependent activation in a whole-brain regression analysis with the Amyg-EFP. Neurocircuitry activation (negative affect, salience, and cognitive control) was correlated with the Amyg-EFP signal. Study 2 showed Amyg-EFP modulation with NF training, but patients received reversed feedback for technical reasons, which limited interpretation of results.
Recorded via scalp EEG, the Amyg-EFP picks up brain activation of high relevance for emotion. Administering Amyg-EFP NF in addition to standardized BPD treatment was shown to be feasible. Clinical utility remains to be investigated.
This review focuses on the evidence for neurotherapeutics for attention deficit/hyperactivity disorder (ADHD). EEG-neurofeedback has been tested for about 45 years, with the latest meta-analyses of ...randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly the dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has been shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.
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