Regulation of ploidy and senescence by the AMPK-related kinase NUAK1.

Senescence is an irreversible cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan. Interestingly, the levels of NUAK1 are upregulated during senescence whereas its ectopic expression triggers a premature senescence. Cells that constitutively express NUAK1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator LATS1, whereas depletion of NUAK1 with shRNA exerts opposite effects. Interestingly, a dominant-negative form of LATS1 phenocopies NUAK1 effects. Moreover, we show that NUAK1 phosphorylates LATS1 at S464 and this has a role in controlling its stability. In summary, our work highlights a novel role for NUAK1 in the control of cellular senescence and cellular ploidy.We thank the members of the Laboratory for helpful discussions. We also thank Virginie Glippa and Julie Bertout for technical assistance. We thank H Esumi for the NUAK1 cDNA, E Hara and H Saya for the LATS1‐encoding vector. This work was carried out with the support of the ‘Association pour la Recherche sur le Cancer’, the ‘Fondation pour la Recherche Médicale Nord Pas de Calais’, the ‘Comité du Pas de Calais de la Ligue Nationale contre le Cancer’, the RTRS Fondation Synergie Lyon Cancer, and the Medical Research Council, UK.S

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

Involvment of oxidative stress in senescence and cancerous initiation of epithelial cells

Après un certain nombre de divisions, les cellules primaires entrent en sénescence, un état caractérisé par des modifications morphologiques, biochimiques et un arrêt de croissance. Deux principaux mécanismes concourent à l'établissement de la sénescence: le raccourcissement Après un certain nombre de divisions, les cellules primaires entrent en sénescence, un état caractérisé par des modifications des télomères et l'accumulation de dommages oxydants. La sénescence est généralement considérée comme une barrière au développement tumoral. Nous montrons dans ce travail que la sénescence pourrait aussi contribuer à l'initiation cancéreuse. En effet, dans des cultures de kératinocytes sénescents nous observons l'émergence systématique de cellules transformées et tumorigènes. Ces cellules se forment à partir d'une fraction de cellules sénescentes, par un mécanisme de mitose atypique. La sénescence des kératinocytes s'accompagne d'une accumulation de dommages oxydants mutagènes (cassures simple brin, guanines oxydées et pontages moléculaires). Par ailleurs, les télomères ne sont que très peu érodés et les voies d'arrêt dans le cycle cellulaire induites par les cassures double-brin ne sont pas activées. Pour comparaison, dans les fibroblastes, qui n'émergent jamais, on observe à la sénescence moins de dommages oxydants dans le noyau, des télomères devenus très courts et l'activation des voies d'arrêt dans le cycle. Ainsi, l'émergence résulterait de l'effet mutagène du stress oxydant associé et nécessiterait des télomères suffisamment longs. En conclusion, nous mettons en évidence dans ces travaux un nouveau mécanisme potentiel de cancérisation des cellules épithéliales, dans lequel la sénescence constituerait l'étape initiale et le stress oxydant jouerait le rôle de carcinogène endogène.After a finite number of divisions, primary cells enter senescence, a state characterized by morphological and biochemical modifications, and by cell cycle arrest. Two mains events promote the establishment of senescence: telomere shortening and cumulative oxidative stress. Senescence is generally considered as a barrier against tumorigenesis. We show in this work that senescence could also contribute to the cancerous initiation. Indeed, in culture of senescent keratinocytes we observe the systematic emergence of transformed and tumorigenic cells. These cells arise from a fraction of the senescent cell population, by a mechanism of atypical mitosis. Keratinocyte senescence is accompanied by an accumulation of mutagenic oxidative damages (single-strand breaks, oxidized guanines, and cross-linkings). ln addition, telomeres are weakly eroded and cell cycle arrest pathways induced by double-strand breaks are not activated. ln comparison, in fibroblasts, which never emerge, we observe less oxidative damages in nucleus, very short telomeres, and the activation of cel! cycle arrest pathways. Hence, emergence would result from mutagenic oxidative stress and would require enough long telomeres. ln conclusion, we highlight in this work a new potential mechanism of epithelial cel! carcinogenesis, wherein senescence would constitute the initial step and oxidative stress would act as an endogenous carcinogen

Rôle du stress oxydant dans la sénescence et l'initiation cancéreuse des cellules épithéliales

Après un certain nombre de divisions, les cellules primaires entrent en sénescence, un état caractérisé par des modifications morphologiques, biochimiques et un arrêt de croissance. Deux principaux mécanismes concourent à l'établissement de la sénescence: le raccourcissement Après un certain nombre de divisions, les cellules primaires entrent en sénescence, un état caractérisé par des modifications des télomères et l'accumulation de dommages oxydants. La sénescence est généralement considérée comme une barrière au développement tumoral. Nous montrons dans ce travail que la sénescence pourrait aussi contribuer à l'initiation cancéreuse. En effet, dans des cultures de kératinocytes sénescents nous observons l'émergence systématique de cellules transformées et tumorigènes. Ces cellules se forment à partir d'une fraction de cellules sénescentes, par un mécanisme de mitose atypique. La sénescence des kératinocytes s'accompagne d'une accumulation de dommages oxydants mutagènes (cassures simple brin, guanines oxydées et pontages moléculaires). Par ailleurs, les télomères ne sont que très peu érodés et les voies d'arrêt dans le cycle cellulaire induites par les cassures double-brin ne sont pas activées. Pour comparaison, dans les fibroblastes, qui n'émergent jamais, on observe à la sénescence moins de dommages oxydants dans le noyau, des télomères devenus très courts et l'activation des voies d'arrêt dans le cycle. Ainsi, l'émergence résulterait de l'effet mutagène du stress oxydant associé et nécessiterait des télomères suffisamment longs. En conclusion, nous mettons en évidence dans ces travaux un nouveau mécanisme potentiel de cancérisation des cellules épithéliales, dans lequel la sénescence constituerait l'étape initiale et le stress oxydant jouerait le rôle de carcinogène endogène.After a finite number of divisions, primary cells enter senescence, a state characterized by morphological and biochemical modifications, and by cell cycle arrest. Two mains events promote the establishment of senescence: telomere shortening and cumulative oxidative stress. Senescence is generally considered as a barrier against tumorigenesis. We show in this work that senescence could also contribute to the cancerous initiation. Indeed, in culture of senescent keratinocytes we observe the systematic emergence of transformed and tumorigenic cells. These cells arise from a fraction of the senescent cell population, by a mechanism of atypical mitosis. Keratinocyte senescence is accompanied by an accumulation of mutagenic oxidative damages (single-strand breaks, oxidized guanines, and cross-linkings). ln addition, telomeres are weakly eroded and cell cycle arrest pathways induced by double-strand breaks are not activated. ln comparison, in fibroblasts, which never emerge, we observe less oxidative damages in nucleus, very short telomeres, and the activation of cel! cycle arrest pathways. Hence, emergence would result from mutagenic oxidative stress and would require enough long telomeres. ln conclusion, we highlight in this work a new potential mechanism of epithelial cel! carcinogenesis, wherein senescence would constitute the initial step and oxidative stress would act as an endogenous carcinogen.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Ion pairing controls rheological properties of “processionary” polyelectrolyte hydrogels

International audienceWe demonstrated recently that polyelectrolytes with cationic moieties along the chain and a single anionic head are able to form physical hydrogels due to the reversible nature of the head-to-body ionic bond. Here we generate a variety of such polyelectrolytes with various cationic moieties and counterion combinations starting from a common polymeric platform. We show that the rheological properties (shear modulus, critical strain) of the final hydrogels can be modulated over three orders of magnitude depending on the cation/anion pair. Our data fit remarkably well within a scaling model involving a supramolecular head-to-tail single file between cross-links, akin to the behaviour of pine-processionary caterpillar. This model allows the quantitative measure of the amount of counterion condensation from standard rheology procedure

MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.

Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2)O(2) overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2)O(2) level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2)O(2). This H(2)O(2)-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria