Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a ...role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis.
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•A role for SETD2 in DSB resection and homologous recombination repair•Histone H3K36me3 is required for homologous recombination•SETD2 and RAD51 suppress mutations arising from microhomology-mediated end-joining•Mutations affecting H3K36me3 levels may promote tumorigenesis
The SETD2 gene encodes the histone H3K36 trimethyltransferase. Pfister et al. now show that human SETD2-dependent H3K36me3 maintains genome stability by promoting error-free DNA repair through homologous recombination (HR). Upon DNA damage, SETD2-depleted cells exhibit reduced DNA resection, impaired recruitment of early HR factors, and increased utilization of the error-prone microhomology-mediated end-joining repair pathway. Eliminating H3K36me3 by overexpressing the oncogene KDM4A also impairs HR. Thus, H3K36me3 suppresses tumorigenesis by promoting accurate DNA repair.
Deregulation of Rho GTPases in cancer Porter, Andrew P.; Papaioannou, Alexandra; Malliri, Angeliki
Small GTPases,
07/2016, Letnik:
7, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In vitro and in vivo studies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has ...identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers.
Suicide is a leading cause of death among youth worldwide. The purpose of the current review was to examine recent cross‐national trends in suicide mortality rates among 10‐ to 19‐year‐olds. This ...study extracted suicide mortality data from the World Health Organization's (WHO) Mortality Database for the most recent year (since 2010) from any country with available high‐quality data (as defined by the WHO's guidelines). Data on access to lethal means (firearms, railways) and measures of economic quality (World Bank Income Group) and inequality (Gini coefficients) were obtained from publicly available data sources. Cross‐national suicide mortality rates in youth were heterogeneous. The pooled estimate across all ages, sexes, and countries was 3.77/100,000 people. The highest suicide rates were found in Estonia, New Zealand, and Uzbekistan. Suicide rates were higher among older compared with younger adolescents and higher among males than females. The most common suicide methods were hanging/suffocation and jumping/lying in front of a moving object or jumping from a height. Firearm and railway access were related to suicide deaths by firearms and jumping/lying, respectively. Economic quality and inequality were not related to overall suicide mortality rates. However, economic inequality was correlated with a higher ratio of male:female suicides. This study provides a recent update of cross‐national suicide trends in adolescents. Findings replicate prior patterns related to age, sex, geographic region, and common suicide methods. New to this review are findings relating suicide method accessibility to suicide mortality rates and the significant association between income inequality and the ratio of male:female suicide. Future research directions include expanding the worldwide coverage to more low‐ and middle‐income countries, examining demographic groupings beyond binary sex and to race/ethnicity within countries, and clarifying factors that account for cross‐national differences in suicide trends.
Read the Commentary on this article at doi: 10.1111/jcpp.13174
DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end ...joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells. By monitoring DSB mis-repair using a sensitive HPRT assay, we found that depletion of HR proteins, including BRCA2, BRCA1 or RPA, resulted in a distinct mutational signature associated with significant increases in break-induced mutation frequencies, deletion lengths and the annealing of short regions of microhomology (2-6 bp) across the break-site. This signature was dependent on CtIP, MRE11, POLQ and PARP, and thus indicative of MMEJ. In contrast to CtIP or MRE11, depletion of BRCA1 resulted in increased partial resection and MMEJ, thus revealing a functional distinction between these early acting HR factors. Together these findings indicate that HR factors suppress mutagenic MMEJ following DSB resection.
The current review provides an evidence base update of psychosocial treatments for self-injurious thoughts and behaviors (SITBs) in youth. A systematic search was conducted of 2 major scientific ...databases (PsycInfo and PubMed) and ClinicalTrials.gov for relevant randomized controlled trials (RCTs) published prior to June 2018. The search identified 26 RCTs examining interventions for SITBs in youth: 17 were included in the 2015 review and 9 trials were new to this update. The biggest change since the prior review was the evaluation of Dialectical Behavior Therapy for adolescents (DBT-A) as the first Level 1: Well-established intervention for reducing deliberate self-harm (composite of nonsuicidal and suicidal self-injury) and suicide ideation in youth and Level 2: Probably efficacious for reducing nonsuicidal self-injury and suicide attempts. Five other interventions were rated as Level 2: Probably efficacious for reducing SITBs in youth, with the new addition of Integrated Family Therapy. This evidence base update indicates that there are a few promising treatments for reducing SITBs in youth. Efficacious interventions typically include a significant family or parent training component as well as skills training (e.g., emotion regulation skills). Aside from DBT-A, few treatments have been examined in more than one RCT. Given that replication by independent research groups is needed to evaluate an intervention as Well-established, future research should focus on replicating the five promising interventions currently evaluated as Probably efficacious. In addition, an important future direction is to develop brief efficacious interventions that may be scalable to reach large numbers of youth.
Type II topoisomerase enzymes are essential for resolving DNA topology problems arising through various aspects of DNA metabolism. In vertebrates two isoforms are present, one of which (TOP2A) ...accumulates on chromatin during mitosis. Moreover, TOP2A targets the mitotic centromere during prophase, persisting there until anaphase onset. It is the catalytically-dispensable C-terminal domain of TOP2 that is crucial in determining this isoform-specific behaviour. In this study we show that, in addition to the recently identified chromatin tether domain, several other features of the alpha-C-Terminal Domain (CTD). influence the mitotic localisation of TOP2A. Lysine 1240 is a major SUMOylation target in cycling human cells and the efficiency of this modification appears to be influenced by T1244 and S1247 phosphorylation. Replacement of K1240 by arginine results in fewer cells displaying centromeric TOP2A accumulation during prometaphase-metaphase. The same phenotype is displayed by cells expressing TOP2A in which either of the mitotic phosphorylation sites S1213 or S1247 has been substituted by alanine. Conversely, constitutive modification of TOP2A by fusion to SUMO2 exerts the opposite effect. FRAP analysis of protein mobility indicates that post-translational modification of TOP2A can influence the enzyme's residence time on mitotic chromatin, as well as its subcellular localisation.
Disrupted sleep has been linked to suicidal thoughts and behavior. Less is known, however, about the underlying mechanisms of this relationship. A more nuanced understanding of the link between sleep ...and suicide may help inform treatment decisions and the development of prevention and intervention strategies. The present study examined daily average sleepiness as a moderator to the relation between same-day passive and active suicide ideation (SI). Fifty-nine young adults (mean age=21.04; SD=2.22) endorsing SI at least twice in the two weeks prior to baseline completed 3-5 daily surveys of sleepiness and SI over two weeks as part of a broader study. Across several indicators of sleepiness (desire to stay awake, desire to fall asleep), passive SI (desire to die, desire to live), and active SI (occurrence, intensity, duration, and controllability), the overall findings demonstrated that daily average sleepiness magnified the relation between same-day passive SI and active SI severity. These findings indicate that being sleepier than usual may increase the likelihood that passive SI transitions to active SI. Future research is needed to test the causal influence of sleepiness on this transition.
•Sleepiness is related to both passive and active suicide ideation•Sleepiness moderates the relation between passive and active suicide ideation•Results are consistent across various indicators of sleepiness and passive ideation
To clarify the role of age in risk associated with drug misuse and binge drinking, this study examines the differential relations of binge drinking and prescription drug misuse to risk of suicidal ...ideation and attempts in young adults of college age (18–24) compared to those above the age of 25.
We used data from the National Survey on Drug Use and Health (NSDUH) for the years 2015 through 2019 (N = 269,078).
The study found that, for adults above college age, the presence of any past-month binge drinking was associated with a higher likelihood of past-year suicide ideation (b = 0.427, OR = 1.532, 95%CI 1.388, 1.692) and attempts (b = 0.637, OR = 1.891, 95%CI 1.271, 2.813) compared to college-aged adults. Similarly, past-month prescription drug misuse showed stronger associations with past-year suicide ideation (b = 0.831, OR = 2.297, 95%CI 1.952, 2.701) and attempts (b = 0.539, OR = 1.715, 95%CI 1.264, 2.327) in adults above college age.
These findings highlight that binge drinking and prescription drug misuse appears to become more strongly associated with suicide ideation and attempts after adults age beyond young adulthood.
How can the ancient relationship between Homer and the Epic Cycle be recovered? Using the most significant research in the field, Andrew Porter questions many ancient and modern assumptions and ...offers alternative perspectives better aligned with ancient epic performance realities and modern epic studies.
Sexual assault is prevalent among undergraduates in Greek-letter organizations (GLO). Prevention efforts promote sexual consent, though few explicitly employ theoretical constructs known to ...positively influence behavior. This study evaluated theory-informed educational posters promoting sexual consent seeking.
Forty undergraduate GLO students (20 female, 20 male) were recruited through in-person, email, and social media solicitation. Data collection was completed March-November 2019 during the spring and fall semesters.
A double-blind randomized controlled trial was conducted. Intervention participants viewed theory-informed educational posters promoting sexual consent.
The intervention group demonstrated more favorable consent intention (
= .024; η
= 0.131) and consent subjective norms (
= .040; η
= 0.109). Intervention group males showed a greater improvement in one of four consent attitudes (
= .045; η
= 0.211).
Brief exposures to theory-informed messaging may help to improve subjective norms and behavioral intent to seek sexual consent among undergraduate GLO members.
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