SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex.

The Sirtuin family of NAD+-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of γH2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3α/ß. This in turn regulates γH2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.

SIRT7 and p53 interaction in embryonic development and tumorigenesis.

p53 is a hallmark tumor suppressor due in part to its role in cell cycle progression, DNA damage repair, and cellular apoptosis; its protein activity interrelates with the Sirtuin family of proteins, major regulators of the cellular response to metabolic, oxidative, and genotoxic stress. In the recent years, mammalian Sirtuin 7 (SIRT7) has emerged as a pivotal regulator of p53, fine-tuning its activity in a context dependent manner. SIRT7 is frequently overexpressed in human cancer, yet its precise role in tumorigenesis and whether it involves p53 regulation is insufficiently understood. Depletion of SIRT7 in mice results in impaired embryo development and premature aging. While p53 activity has been suggested to contribute to tissue specific dysfunction in adult Sirt7 -/- mice, whether this also applies during development is currently unknown. By generating SIRT7 and p53 double-knockout mice, here we show that the demise of SIRT7-deficient embryos is not the result of p53 activity. Notably, although SIRT7 is commonly considered an oncogene, SIRT7 haploinsufficiency increases tumorigenesis in p53 knockout mice. Remarkably, in specific human tumors harboring p53 mutation, we identified that SIRT7 low expression correlates with poor patient prognosis. Transcriptomic analysis unveils a previously unrecognized interplay between SIRT7 and p53 in epithelial-to-mesenchymal transition (EMT) and extracellular matrix regulation with major implications for our understanding of embryonic development and tumor progression.

SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1.

Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.

SIRT7 promotes chromosome synapsis during prophase I of female meiosis.

Sirtuins are NAD+-dependent protein deacylases and ADP-ribosyltransferases that are involved in a wide range of cellular processes including genome homeostasis and metabolism. Sirtuins are expressed in human and mouse oocytes yet their role during female gamete development are not fully understood. Here, we investigated the role of a mammalian sirtuin member, SIRT7, in oocytes using a mouse knockout (KO) model. Sirt7 KO females have compromised fecundity characterized by a rapid fertility decline with age, suggesting the existence of a diminished oocyte pool. Accordingly, Sirt7 KO females produced fewer oocytes and ovulated fewer eggs. Because of the documented role of SIRT7 in DNA repair, we investigated whether SIRT7 regulates prophase I when meiotic recombination occurs. Sirt7 KO pachynema-like staged oocytes had approximately twofold increased γH2AX signals associated with regions with unsynapsed chromosomes. Consistent with the presence of asynaptic chromosome regions, Sirt7 KO oocytes had fewer MLH1 foci (~one less), a mark of crossover-mediated repair, than WT oocytes. Moreover, this reduced level of crossing over is consistent with an observed twofold increased incidence of aneuploidy in Metaphase II eggs. In addition, we found that acetylated lysine 18 of histone H3 (H3K18ac), an established SIRT7 substrate, was increased at asynaptic chromosome regions suggesting a functional relationship between this epigenetic mark and chromosome synapsis. Taken together, our findings demonstrate a pivotal role for SIRT7 in oocyte meiosis by promoting chromosome synapsis and have unveiled the importance of SIRT7 as novel regulator of the reproductive lifespan.

SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina.

Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.

Food craving and consumption evolution in patients starting treatment with clozapine.

BACKGROUND: Antipsychotic-induced weight gain has been especially related to clozapine and olanzapine. Underlying mechanisms in relation to food preferences with an increased food craving and consumption of specific nutrients have not been extensively studied in patients with serious mental illness (SMI). We aim to describe specific food preferences (craving) and subsequent food consumption in SMI patients starting clozapine, as well as their possible relation to weight and body mass index (BMI). METHODS: An observational prospective follow-up study (18 weeks) was conducted in a cohort of 34 SMI patients who started clozapine due to resistant-psychotic symptoms. Anthropometric measures, Food Craving Inventory (FCI), and a food consumption frequency questionnaire were evaluated at baseline, weeks 8 and 18 of treatment. Statistical analysis included generalized estimating equations models with adjustment for potential confounding factors. RESULTS: No longitudinal changes over time were found across the different food craving scores after 18 weeks of treatment. However, adjusted models according to BMI status showed that the normal weight (NW) group presented an increased score for the "complex carbohydrates/proteins" food cravings (- 0.67; 95% CI [- 1.15, - 0.19]; P = 0.010), while baseline scores for "fast-food fats" cravings were significantly higher in the overweight/obese (OWO) group in comparison with NW patients (NW, 2.05; 95% CI [1.60, 2.49]; OWO, 2.81, 95% CI [2.37, 3.25]; P = 0.016). When considering if food craving could predict weight gain, only increments in "fast-food fats" cravings were associated (ß = - 5.35 ± 1.67; 95% CI [- 8.64, - 2.06]; P = 0.001). CONCLUSIONS: No longitudinal differences were found for any of the food craving scores evaluated; however, in the NW group, food craving for "complex carbohydrates/proteins" changed. Thus, changes in "fast-food fats" cravings predicted weight increase in this sample. Interventions targeting food preferences may help to mitigate weight gain in patients starting treatment with clozapine.

Antipsychotic-induced weight gain and birth weight in psychosis: A fetal programming model.

Antipsychotic induced weight gain is a frequent reason for treatment discontinuation in psychosis, subsequently increasing the risk of relapse and negatively affecting patient well-being. The metabolic effect of weight gain and the subsequent risk of obesity constitute a major medical problem on the long term. Despite its consequences, to date few risk factors have been identified (age, gender, body mass index at baseline), with some authors suggesting the implication of early life stressful events, such as perinatal conditions. We aim to describe if a surrogate marker of intrauterine environment (birth weight) might predict weight gain in a cohort of 23 antipsychotic naïve patients at the onset of the psychotic disease evaluated during 16 weeks with olanzapine treatment and in another cohort of 24 psychosis-resistant patients initiating clozapine assessed for 18 weeks. Two independent linear mixed model analyses were performed in each cohort of patients, with prospective weight gain as the dependent variable, age, gender, body mass index, duration of treatment and time as independent variables. Only in naïve patients, weight gain due to antipsychotics was significantly associated with birth weight, while male gender and body mass index at baseline were associated in both cohorts of patients. Treatment-resistant psychotic patients under clozapine were older, had previous antipsychotic treatment and more years of disease, confounders that might have influence a non significant association. Our results suggest that early environmental events might be playing a role in weight evolution in naïve patients treated with antipsychotics.

Predictive study of academic stress with the irritable bowel syndrome in medicine students at a public university in Mexico.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with stress, which may appear by an educational context, given that students are exposed to demands in the academic environment during their education process that may lead to developing diseases. This study reports on the relationship between the IBS and academic stress and compares results of men and women. METHODS: A random survey was made of 561 medicine students at a public university in Mexico. The ROMA III criteria were used for the IBS and the Academic Stress Inventory for academic stress. A multiple regression analysis was made. RESULTS: The results showed that students with academic overload and lack of time are at risk for developing the IBS. CONCLUSIONS: Therefore, the recommendation is to implement educational programs aiming at self-care as well as gaining knowledge about academic stress-related factors and the physical responses that may result in repercussions with serious consequences for student life such as pain, disease and dropping out of school.

SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway.

Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.

Mammalian HP1 Isoforms Have Specific Roles in Heterochromatin Structure and Organization.

HP1 is a structural component of heterochromatin. Mammalian HP1 isoforms HP1α, HP1ß, and HP1γ play different roles in genome stability, but their precise role in heterochromatin structure is unclear. Analysis of Hp1α-/-, Hp1ß-/-, and Hp1γ-/- MEFs show that HP1 proteins have both redundant and unique functions within pericentric heterochromatin (PCH) and also act globally throughout the genome. HP1α confines H4K20me3 and H3K27me3 to regions within PCH, while its absence results in a global hyper-compaction of chromatin associated with a specific pattern of mitotic defects. In contrast, HP1ß is functionally associated with Suv4-20h2 and H4K20me3, and its loss induces global chromatin decompaction and an abnormal enrichment of CTCF in PCH and other genomic regions. Our work provides insight into the roles of HP1 proteins in heterochromatin structure and genome stability.

Sirtuins and DNA damage repair: SIRT7 comes to play.

Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7-/- mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability. SIRT7 is recruited to DSBs, where it specifically deacetylates histone H3 at lysine 18 and affects the focal accumulation of the DNA damage response factor 53BP1, thus influencing the efficiency of repair. Here, we integrate our findings with the current knowledge on the mode of action of other sirtuin family members in DNA repair. We emphasize their capacity to regulate chromatin structure as a response to DNA damage within the constraints imposed by cellular status.

An HP1 isoform-specific feedback mechanism regulates Suv39h1 activity under stress conditions.

The presence of H3K9me3 and heterochromatin protein 1 (HP1) are hallmarks of heterochromatin conserved in eukaryotes. The spreading and maintenance of H3K9me3 is effected by the functional interplay between the H3K9me3-specific histone methyltransferase Suv39h1 and HP1. This interplay is complex in mammals because the three HP1 isoforms, HP1α, ß, and γ, are thought to play a redundant role in Suv39h1-dependent deposition of H3K9me3 in pericentric heterochromatin (PCH). Here, we demonstrate that despite this redundancy, HP1α and, to a lesser extent, HP1γ have a closer functional link to Suv39h1, compared to HP1ß. HP1α and γ preferentially interact in vivo with Suv39h1, regulate its dynamics in heterochromatin, and increase Suv39h1 protein stability through an inhibition of MDM2-dependent Suv39h1-K87 polyubiquitination. The reverse is also observed, where Suv39h1 increases HP1α stability compared HP1ß and γ. The interplay between Suv39h1 and HP1 isoforms appears to be relevant under genotoxic stress. Specifically, loss of HP1α and γ isoforms inhibits the upregulation of Suv39h1 and H3K9me3 that is observed under stress conditions. Reciprocally, Suv39h1 deficiency abrogates stress-dependent upregulation of HP1α and γ, and enhances HP1ß levels. Our work defines a specific role for HP1 isoforms in regulating Suv39h1 function under stress via a feedback mechanism that likely regulates heterochromatin formation.

53BP1 ablation rescues genomic instability in mice expressing 'RING-less' BRCA1.

BRCA1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2-deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N-terminal RING domain. This "RING-less" BRCA1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD51 foci form in cells expressing RING-less BRCA1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1, which encodes the DNA damage response factor 53BP1, and mice expressing RING-less BRCA1 do not show an increased susceptibility to tumors in the absence of 53BP1. Genomic instability in cells expressing RING-less BRCA1 correlates with the loss of BARD1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA1-BARD1 in genomic integrity that is independent of RAD51 loading.

Psychophysiological Manifestations Associated With Stress in Students of a Public University in Mexico.

PROBLEM: Academic stress is defined as a physiological, emotional, cognitive, and behavioral activation reaction to stimuli. This stress can impact students' ability to cope with the school environment. OBJECTIVE: To identify the psychophysiological manifestations associated with high-level academic stress in public university students in Mexico. METHODS: A representative random sampling of 527 students was evaluated during 2012. The Academic Stress Symptom Inventory and the Rossi classification were used; data were analyzed with a binary logistic regression analysis to estimate association between psychophysiological manifestations and the high level of academic stress in public university students. FINDINGS: Results indicated a meaningful association between high levels of academic stress situations and psychophysiological manifestations such as concentration and memory problems, mental blocks and chronic fatigue, drowsiness, and despair. CONCLUSION: Identifying academic stress situations and students' maladaptive responses may help promote timely attention to psychophysiological manifestations before they exacerbate and become harmful to college students' health.

SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair.

Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N-terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7-knockout mice suffer from partial embryonic lethality and a progeroid-like phenotype. Consistently, SIRT7-deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1-dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double-strand breaks (DSBs), thereby influencing the efficiency of non-homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7-mediated H3K18 deacetylation and the maintenance of genome integrity.

Incapacidad permanente debido a hipoacusia conductiva y neurosensorial identificadas en diferentes delegaciones del Instituto Mexicano del Seguro Social / Permanent disability due to conductive and sensorineural hearing loss detected in different regional offices in the Mexican Social Security Institute

La hipoacusia se refiere a un daño en la capacidad de audición de una persona. La investigación es retrospectiva y comparativa; el objetivo es evaluar el comportamiento de las enfermedades de trabajo por hipoacusia conductiva y neurosensorial, con incapacidades permanentes. El análisis se dio en los años 2010, 2011 y 2012 en los estados mexicanos de Coahuila, Hidalgo, Nuevo León y Veracruz Sur. En el año 2010 en los estados antes mencionados por hipoacusia conductiva y neurosensorial se tuvo un promedio de 186 enfermedades de trabajo. En 2011 y 20012 enfermedades de trabajo por hipoacusia fueron 173 y 163, respectivamente. Las incapacidades permanentes por hipoacusia conductiva y neurosensorial, en los estados antes mencionados en el año 2010 el promedio fueron de 494. En el 2011 y 2012 el promedio de enfermedades por hipoacusia fue de 410 y 301, respectivamente. Los promedios se obtuvieron de la información que se obtuvo de la página electrónica del Instituto Mexicano del Seguro Social en los años mencionados. En el Estado de Coahuila en el año 2012 se dio el mayor número de enfermedades de trabajo por hipoacusia. La hipoacusia constituye un problema de salud ocupacional en el Instituto Mexicano del Seguro Social. Es necesario más aplicación de los procedimientos seguros de trabajo y mayor supervisión en su aplicación por los involucrados en seguridad e higiene(AU)

Síntomas psicofisiológicos predictores del estrés en inmigrantes mexicanos en Canadá / Psychophysiological symptoms predictive of stress in Mexican immigrants in Canada

La emigración es un fenómeno relacionado con el estrés, el cual se manifiesta por las pérdidas implícitas en la salida del país de origen. Este artículo reporta la relación del estrés percibido con síntomas psicofisiológicos, la edad, género y años de residencia de inmigrantes mexicanos que radican en Edmonton, Canadá. Se encuestó a 237 inmigrantes seleccionados aleatoriamente, durante el año 2013. Se utilizó el cuestionario Perfil de Estrés y el Inventario de Síntomas de Estrés. Se encontró relación entre el estrés percibido y síntomas físicos (e.g., manos o pies fríos, dolor de cuello o espalda y fatiga), síntomas psicológicos (sentirse deprimido, ansioso e insomnio), y género femenino. La identificación de la percepción de estresores de salud, trabajo, financieros, familia, entorno social y ambiental puede prevenir sintomatología psicofisiológica en inmigrantes

Emigration is a stress-related phenomenon that is manifested depending on the losses perceived when leaving one’s own country of origin. This article reports the relationship between perceived stress and psychophysiological symptoms, age, gender and years of residence of Mexican immigrants living in Edmonton, Canada. Two hundred and thirty seven randomly selected immigrants were surveyed during the year 2013. A relationship was found between perceived stress and physical symptoms (cold hands and feet, neck and backaches, and fatigue), psychological symptoms (feeling depressed, anxiety and insomnia), and female gender. Assessing the symptomology of perceived stress in immigrants’ health, work, finance, family and social and environmental settings may offer an opportunity for efficient intervention

MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3.

Conquering obesity has become a major socioeconomic challenge. Here, we show that reduced expression of the miR-25-93-106b cluster, or miR-93 alone, increases fat mass and, subsequently, insulin resistance. Mechanistically, we discovered an intricate interplay between enhanced adipocyte precursor turnover and increased adipogenesis. First, miR-93 controls Tbx3, thereby limiting self-renewal in early adipocyte precursors. Second, miR-93 inhibits the metabolic target Sirt7, which we identified as a major driver of in vivo adipogenesis via induction of differentiation and maturation of early adipocyte precursors. Using mouse parabiosis, obesity in mir-25-93-106b(-/-) mice could be rescued by restoring levels of circulating miRNA and subsequent inhibition of Tbx3 and Sirt7. Downregulation of miR-93 also occurred in obese ob/ob mice, and this phenocopy of mir-25-93-106b(-/-) was partially reversible with injection of miR-93 mimics. Our data establish miR-93 as a negative regulator of adipogenesis and a potential therapeutic option for obesity and the metabolic syndrome.

Defunciones por riesgo de trabajo en el trienio 2010-2012 en el estado de Jalisco, México / Deaths by work risks in the triennium 2010- 2012 in the state of Jalisco, Mexico

El estudio es retrospectivo comparativo, con el objetivo de evaluar el comportamiento de las defunciones por riesgos de trabajo en el trienio 2010-2012 en el estado de Jalisco, México. En el trienio se produjeron 109, 123 y 130, respectivamente. Se revisaron los formatos existentes en lo referente a riesgos de trabajo, de la División de Información en Salud (ST-5) del Instituto Mexicano del Seguro Social, dándose una accidentalidad de 175 498 riesgos de trabajo, de los cuales 137 923 fueron accidentes de trabajo, 36 864 accidentes de trayecto y 711 enfermedades de trabajo. En el año 2012 ocurrió el mayor número de accidentes de trabajo, 47 762, 13 342 accidentes de trayecto y 376 enfermedades de trabajo. En el mismo año por accidente de trabajo ocurrieron 102 defunciones. En el 2011 por accidente de trayecto hubo 33 defunciones. En el 2012 por enfermedades de trabajo se produjeron 4 defunciones. Las defunciones según la naturaleza de la lesión y sexo, en el año 2010, fueron varios de frecuencia menor en hombres (36) y fractura de hueso del cráneo y de cara en mujeres (4). En 2011 el traumatismo de la cabeza (49) en hombres y 4 en mujeres, fueron las causas de las defunciones. Y en 2012 traumatismo de la cabeza en hombres (52) y 4 traumatismo del tórax en mujeres. Es necesario más aplicación de los procedimientos seguros de trabajo y mayor supervisión en su aplicación por los involucrados en seguridad e higiene en el trabajo(AU)

Social representat ions of dental treatment in a group of environmental health graduate students in Lima (Peru).

UNLABELLED: Social representations are a type of common sense knowledge shared by different groups based on their experience. This study identified the social representations of dental practice in a group of environmental health graduate students in Lima, Peru. METHOD: We interviewed 25 graduate students using a "focus group" technique and a semi-structured guide. Three groups were formed with purposive sampling. The data were collected during the years 2010-2011, and analyzed using open, axial, selective coding with Atlas-Ti software. RESULTS: Three substantive categories were identified: dental practice, characteristics of the dental care provider and dental practice setting. The social representations that the students identified with dental practice were fear and pain. CONCLUSIONS: The negative social representations of dental practice may affect viability and adherence to treatment, so it is important to identify them in time in order to intervene effectively.