The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability.

Regulation of DNA replication and cell division is essential for tissue growth and maintenance of genomic integrity and is particularly important in tissues that undergo continuous regeneration such as mammary glands. We have previously shown that disruption of the KRAB-domain zinc finger protein Roma/Zfp157 results in hyperproliferation of mammary epithelial cells (MECs) during pregnancy. Here, we delineate the mechanism by which Roma engenders this phenotype. Ablation of Roma in MECs leads to unscheduled proliferation, replication stress, DNA damage, and genomic instability. Furthermore, mouse embryonic fibroblasts (MEFs) depleted for Roma exhibit downregulation of p21Cip1 and geminin and have accelerated replication fork velocities, which is accompanied by a high rate of mitotic errors and polyploidy. In contrast, overexpression of Roma in MECs halts cell-cycle progression, whereas siRNA-mediated p21Cip1 knockdown ameliorates, in part, this phenotype. Thus, Roma is an essential regulator of the cell cycle and is required to maintain genomic stability.This work was supported by a PhD studentship from A*STAR Singapore to T.L.F.H. and funding from the Medical Research Council to C.J.W. G.G. and J.E.S. are supported by an MRC core grant to LMB (U105178808).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.celrep.2016.03.07

The Clusters of Health-Risk Behaviours and Mental Wellbeing and Their Sociodemographic Correlates: A Study of 15,366 ASEAN University Students

Background This study investigated, through cluster analysis, the associations between behavioural characteristics, mental wellbeing, demographic characteristics, and health among university students in the Association of Southeast Asian Nations (ASEAN) University Network – Health Promotion Network (AUN-HPN) member universities. Methods Data were retrieved from a cross-sectional self-administered online survey among undergraduate students in seven ASEAN countries. A two-step cluster analysis was employed, with cluster labels based on the predominant characteristics identified within the clusters. The ‘healthy’ cluster was assigned as the reference group for comparisons using multinomial logistic regression analysis. Results The analytic sample size comprised 15,366 university students. Five clusters of student-types were identified: (i) ‘Healthy’ (n = 1957; 12.7%); (ii) ‘High sugary beverage consumption’ (n = 8482; 55.2%); (iii) ‘Poor mental wellbeing’ (n = 2009; 13.1%); (iv) ‘Smoker’ (n = 1364; 8.9%); and (v) ‘Alcohol drinker’ (n = 1554; 10.1%). Being female (OR 1.28, 95%CI 1.14, 1.45) and being physically inactive (OR 1.20, 95%CI 1.04, 1.39) increased the odds of belonging to the ‘High sugary beverage consumption’ cluster. Being female (OR 1.21, 95%CI 1.04, 1.41), non-membership in a sports club (OR 1.83, 95%CI 1.43, 2.34) were associated with ‘Poor mental wellbeing’. Obesity (OR 2.03, 95%CI 1.47, 2.80), inactively commuting to campus (OR 1.34, 95%CI 1.09, 1.66), and living in high-rise accommodation (OR 2.94, 95%CI 1.07, 8.07) were associated with membership in the ‘Smoker’ cluster. Students living in The Philippines, Singapore, Thailand, and Vietnam had a higher likelihood of being alcohol drinkers, compared with those who lived in Brunei. Conclusions ASEAN university students exhibited health-risk behaviours that typically clustered around a specific health behaviour and mental wellbeing. The results provided support for focusing interventions on one dominant health-risk behaviour, with associated health-risk behaviours within clusters being potential mediators for consideration

Oncolytic Virotherapy: Harnessing Nature to Treat High-Grade Gliomas and Metastatic Cancer

https://openworks.mdanderson.org/sumexp21/1170/thumbnail.jp

Activation of the ATR kinase by the RPA-binding protein ETAA1

Activation of the ATR kinase following perturbations to DNA replication relies on a complex mechanism involving ATR recruitment to RPA-coated single-stranded DNA via its binding partner ATRIP and stimulation of ATR kinase activity by TopBP1. Here, we discovered an independent ATR activation pathway in vertebrates, mediated by the uncharacterized protein ETAA1 (Ewing's tumour-associated antigen 1). Human ETAA1 accumulates at DNA damage sites via dual RPA-binding motifs and promotes replication fork progression and integrity, ATR signalling and cell survival after genotoxic insults. Mechanistically, this requires a conserved domain in ETAA1 that potently and directly stimulates ATR kinase activity independently of TopBP1. Simultaneous loss of ETAA1 and TopBP1 gives rise to synthetic lethality characterized by massive genome instability and abrogation of ATR-dependent signalling. Our findings demonstrate that parallel TopBP1-and ETAA1-mediated pathways underlie ATR activation and that their combined action is essential for coping with replication stress

Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty

Mammary gland development begins with the appearance of epithelial placodes that invaginate, sprout, and branch to form small arborized trees by birth. The second phase of ductal growth and branching is driven by the highly invasive structures called terminal end buds (TEBs) that form at ductal tips at the onset of puberty. Ectodysplasin (Eda), a tumor necrosis factor-like ligand, is essential for the development of skin appendages including the breast. In mice, Eda regulates mammary placode formation and branching morphogenesis, but the underlying molecular mechanisms are poorly understood. Fibroblast growth factor (Fgf) receptors have a recognized role in mammary ductal development and stem cell maintenance, but the ligands involved are ill-defined. Here we report that Fgf20 is expressed in embryonic mammary glands and is regulated by the Eda pathway. Fgf20 deficiency does not impede mammary gland induction, but compromises mammary bud growth, as well as TEB formation, ductal outgrowth and branching during puberty. We further show that loss of Fgf20 delays formation of Eda-induced supernumerary mammary buds and normalizes the embryonic and postnatal hyperbranching phenotype of Eda overexpressing mice. These findings identify a hitherto unknown function for Fgf20 in mammary budding and branching morphogenesis.Peer reviewe

Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia.

BACKGROUND: Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking. METHODS: Young adult (12-16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and muscle weights, and muscle fiber diameters were measured. Body composition was determined by Piximus. Plasma analyte levels were determined by bead array assay. RESULTS: Survival and weight loss were dependent upon burn size. The body weight nadir in burned mice was 14 days, at which time we observed reductions in total body mass, lean carcass mass, individual muscle weights, and muscle fiber cross-sectional area. Muscle loss was associated with increased expression of the muscle ubiquitin ligase, MuRF1. Burned mice also exhibited reduced fat mass and bone mineral density, concomitant with increased liver, spleen, and heart mass. Recovery of initial body weight occurred at 35 days; however, burned mice exhibited hyperphagia and polydipsia out to 80 days. Burned mice had significant increases in serum cytokine, chemokine, and acute phase proteins, consistent with findings in human burn subjects. CONCLUSIONS: This study describes a mouse model that largely mimics human pathophysiology following severe burn injury. These baseline data provide a framework for mouse-based pharmacological and genetic investigation of burn-injury-associated cachexia