Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.

BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.We thank beamline scientists at Diamond Light Source for help during data collection of crystal and SAXS. The crystallization experiments were performed in the Crystallographic X-ray facility at the Department of Biochemistry, University of Cambridge. We are grateful to the Facility Manager, Dr. Dimitri Chirgadze, for his assistance in using these facilities and advice during crystal structure determination. We also thank Dr. Yanfen Hu (University of Texas Health Science Center at San Antonia) for the pFlag-BRCA1 plasmid and Dr. Angela Pacitto (University of Cambridge) for reading the manuscript. We thank Dr. Adriana Paulucci-Holthanuzen (Department of Genetics-MD Anderson Microscopy Core Facility) for assistance with images and analysis. Q.W., T.O. and T.L.B. are funded by the Wellcome Trust (Grant 093167/Z/10/Z). A.P. is an awardee of the Schissler Foundation Fellowship, the Center for Cancer Epigenetics Scholarship and the Andrew Sowell-Wade Huggins Scholarship. This work is supported by the National Institutes of Health grant (CA155025 to B.W) with funds from the University of Texas MD Anderson Cancer Center (IRG, Center for Cancer Epigenetics, Center for Genetics and Genomics Pilot Award). S.M. is funded by the Medical Research Council (grant 98101 to C.V.R.) and C.V.R. is a Royal Society Research Professor. T.K.F and B.X. are supported by National Institutes of Health grant (R01CA138804 to B.X).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.molcel.2015.12.01

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion

Pathogenic Variants in MT-ATP6: A United Kingdom-Based Mitochondrial Disease Cohort Study

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-31

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Suicide crisis calls to emergency services: Cohort profile and findings from a data linkage study in Queensland, Australia

Background and Aims: Police and paramedics play a crucial role in responding to suicide crises in the community. However, little is known about the nature, extent, precipitating factors, pathways and outcomes of a suicide-related call to emergency services and what responses will most effectively and compassionately meet the needs of those in crisis. Partners in Prevention: Understanding and Enhancing First Responses to Suicide Crisis Situations (PiP) was established to address these knowledge gaps. Methods: This article describes (1) the methodology used to construct the PiP dataset, a population-wide linked dataset that investigates the characteristics and health pathways of individuals in Queensland who were the subject of a suicide-related call to police or paramedics; and (2) preliminary findings on service demand, demographics and health services utilisation. Results: We identified 219,164 suicide-related calls to Queensland Police Service or Queensland Ambulance Service that were made over the 3-year period 1 February 2014 to 31 January 2017. A total of 70,893 individuals were identifiable via records linkage. The cohort linked to more than 7,000,000 health records. We estimated that police or paramedics in Queensland received on average 209 calls per day, with increases year on year over the study period. Analysis of demographic data highlighted the heterogeneous nature of this cohort and important demographic variations between individuals in contact with police versus ambulance services. Discussion: The PiP dataset provides a strong foundation for a multi-modal dataset that can be built on over time, both cross-sectionally and longitudinally. Further linkages to Medicare Benefits Schedule, Pharmaceutical Benefits Scheme and social care datasets are planned. Conclusion: Detailed population-level analysis that data linkage can provide is critical to improving understanding and responses to suicide crisis situations. The PiP study is a world first and provides a unique opportunity to improve responses to this public health problem.</p

A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease

Abstract Many aging individuals accumulate the pathology of Alzheimer’s disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD

The Role of Romantic Involvement and Social Support in Italian Adolescent Mothers' Live

This study examined the experience of mothering in adolescence in the context of romantic involvement and social support. 30 adolescent mothers completed measures of adolescent self-development and motherhood, romantic relationship experience, availability of and satisfaction with social support, and parenting stress. Findings suggest that young mothers benefit greatly from the support of a partner, as evidenced by a more functional understanding of motherhood and the maternal role, greater satisfaction with social support, and lower levels of psychological distress. Education on social support should be made available to young mothers to address stress associated with adolescent parenting

Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study.

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315