Interplay of the Ubiquitin Proteasome System with Nucleotide Excision Repair

Dit proefschrift kwam tot stand binnen de vakgroep Celbiologie en Genetica van de faculteit der Geneeskunde en Gezondheidswetenschappen van de Erasmus Universiteit Rotterdam. De vakgroep maakt deel uit van het Medisch Genetisch Centrum Zuid-West Nederland. Het onderzoek is financieel ondersteund door het Center for Biomedical Genetics, de Koninklijke Nederlandse Akademie van Wetenschappen en de Nederlandse Organisatie voor Wetenschappelijk Onderzoek.The genetic information stored in the DNA encodes directly or indirectly for all processes important for life. The nucleic acid order of the DNA is (via RNA) translated into proteins. The various proteins have distinct and vital functions that are important for the catalysis of the distinct processes in our cells, furthermore they function in the structures in and outside our cells as well. During the live cycle of every cell a constant challenge from both exogenous as endogenous sources potentially damages both proteins and DNA. Proteins can be easily be replaced by the synthesis of new ones. In contrast however, DNA as the carrier of information itself cannot be replaced and therefore, damage ne

Perinatal psychiatric episodes: a population-based study on treatment incidence and prevalence

Perinatal psychiatric episodes comprise various disorders and symptom severity, which are diagnosed and treated in multiple treatment settings. To date, no studies have quantified the incidence and prevalence of perinatal psychiatric episodes treated in primary and secondary care, which we aimed to do in the present study. We designed a descriptive prospective study and included information from Danish population registers to study first-time ever and recurrent psychiatric episodes during the perinatal period, including treatment at psychiatric facilities and general practitioners (GPs). This was done for all women who had records of one or more singleton births from 1998 until 2012. In total, we had information on 822 439 children born to 491 242 unique mothers. Results showed first-time psychiatric episodes treated at inpatient facilities were rare during pregnancy, but increased significantly shortly following childbirth (0.02 vs 0.25 per 1000 births). In comparison, first-time psychiatric episodes treated at outpatient facilities were more common, and showed little variation across pregnancy and postpartum. For every single birth resulting in postpartum episodes treated at inpatient psychiatric facilities, 2.5 births were followed by an episode treated at outpatient psychiatric facility and 12 births by GP-provided pharmacological treatment. We interpret our results the following way: treated severe and moderate psychiatric disorders have different risk patterns in relation to pregnancy and childbirth, which suggests differences in the underlying etiology. We further speculate varying treatment incidence and prevalence in pregnancy vs postpartum may indicate that the current Diagnostic and Statistical Manual of Mental Disorders-5 peripartum specifier not adequately describes at-risk periods across moderate and severe perinatal psychiatric episodes

Mindfulness During Pregnancy and Parental Stress in Mothers Raising Toddlers

Objectives: Parental stress has been associated with adverse child outcomes and maternal functioning. Yet, maternal factors during pregnancy that can potentially protect against later parental stress, such as mindfulness, have not been studied. Therefore, we aimed to address the possible associations between prenatal mindfulness and levels of parental stress in mothers raising toddlers. Methods: Women in the current study (n = 165) were prospectively followed from pregnancy until 3 years after childbirth, as part of a longitudinal population based cohort (HAPPY study). At 22 weeks of pregnancy, women completed the Three Facet Mindfulness Questionnaire–Short Form (TFMQ-SF) to assess facets of mindfulness (acting with awareness, non-judging, and non-reacting). Women completed the Parenting Stress Questionnaire (PSQ) 3 years after childbirth, reporting on three components of parental stress: (1) parent-child relationship problems, (2) parenting problems, and (3) role restriction. Results: Results of multiple linear regression analyses showed that the acting with awareness facet of mindfulness during pregnancy was a significant predictor of fewer parent-child relationship problems and parenting problems, even when adjusted for prenatal and maternal distress and child behavior problems. Higher levels of non-reacting during pregnancy were also significantly associated with fewer parenting problems in mothers raising toddlers. Conclusions: The current study emphasizes that mindfulness during pregnancy may be a protective factor for later parental stress. More research is needed to confirm these findings and to evaluate the possible benefit of a mindfulness intervention training during pregnancy on parenting and child outcomes

Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated Topoisomerase I to promote genome stability

Peer reviewedPublisher PD

Blood-based immune-endocrine biomarkers of treatment response in depression

Antidepressant treatment for major depressive disorder remains suboptimal with response rates of just over 50%. Although treatment guidelines, algorithms and clinical keys are available to assist the clinician, the process of finding an effective pharmacotherapy to maximise benefit for the individual patient is largely by "trial and error" and remains challenging. This highlights a clear need to identify biomarkers of treatment response to help guide personalised treatment strategies. We have carried out the largest multiplex immunoassay based longitudinal study to date, examining up to 258 serum markers involved in immune, endocrine and metabolic processes as potential biomarkers associated with treatment response in 332 depression patients recruited from four independent clinical centres. We demonstrated for the first time that circulating Apolipoprotein A-IV, Endoglin, Intercellular Adhesion Molecule 1, Tissue Inhibitor of Metalloproteinases 1, Plasminogen Activator Inhibitor 1, Thrombopoietin, Complement C3, Hepatocyte Growth Factor and Insulin-like Growth Factor-Binding Protein 2 were associated with response to different antidepressants. In addition, we showed that specific sets of immune-endocrine proteins were associated with response to Venlafaxine (serotonin-norepinephrine reuptake inhibitor), Imipramine (tricyclic antidepressant) and other antidepressant drugs. However, we were not able to reproduce the literature findings on BDNF and TNF-$\alpha$, two of the most commonly reported candidate treatment response markers. Despite the need for extensive validation studies, our preliminary findings suggest that a pre-treatment immune-endocrine profile may help to determine a patient's likelihood to respond to specific antidepressant and/or alternative treatments such as anti-inflammatory drugs, providing hope for future personalised treatment approaches.Drs Chan, Cooper and Prof. Bahn were supported by grants from the Stanley Medical Research Institute (no. 07R-1888). The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10- 000-1002) and is supported by participating universities (VU University Medical Center, Arkin, Leiden University Medical Center, University Medical Center Groningen

Postpartum psychiatric disorders

Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive–compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal–child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential

Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

BAG3 is a multi-domain hub that connects two classes of chaperones, small heat shock proteins (sHSPs) via two isoleucine-proline-valine (IPV) motifs and Hsp70 via a BAG domain.\ua0Mutations in either the IPV or BAG domain of BAG3 cause a dominant form of myopathy, characterized by protein aggregation in both skeletal and cardiac muscle tissues. Surprisingly, for both disease mutants, impaired chaperone binding is not sufficient to explain disease phenotypes. Recombinant mutants are correctly folded, show unaffected Hsp70 binding but are impaired in stimulating Hsp70-dependent client processing. As a consequence, the mutant BAG3 proteins become the node for a dominant gain of function causing aggregation of itself, Hsp70, Hsp70 clients and tiered interactors within the BAG3 interactome. Importantly, genetic and pharmaceutical interference with Hsp70 binding completely reverses stress-induced protein aggregation for both BAG3 mutations. Thus, the gain of function effects of BAG3 mutants act as Achilles heel of the HSP70 machinery

Two Nuclear Localization Signals in USP1 Mediate Nuclear Import of the USP1/UAF1 Complex

The human deubiquitinase USP1 plays important roles in cancer-related processes, such as the DNA damage response, and the maintenance of the undifferentiated state of osteosarcoma cells. USP1 deubiquitinase activity is critically regulated by its interaction with the WD40 repeat-containing protein UAF1. Inhibiting the function of the USP1/UAF1 complex sensitizes cancer cells to chemotherapy, suggesting that this complex is a relevant anticancer target. Intriguingly, whereas UAF1 has been reported to locate in the cytoplasm, USP1 is a nuclear protein, although the sequence motifs that mediate its nuclear import have not been functionally characterized. Here, we identify two nuclear localization signals (NLSs) in USP1 and show that these NLSs mediate the nuclear import of the USP1/UAF1 complex. Using a cellular relocation assay based on these results, we map the UAF1-binding site to a highly conserved 100 amino acid motif in USP1. Our data support a model in which USP1 and UAF1 form a complex in the cytoplasm that subsequently translocates to the nucleus through import mediated by USP1 NLSs. Importantly, our findings have practical implications for the development of USP1-directed therapies. First, the UAF1-interacting region of USP1 identified here might be targeted to disrupt the USP1/UAF1 interaction with therapeutic purposes. On the other hand, we describe a cellular relocation assay that can be easily implemented in a high throughput setting to search for drugs that may dissociate the USP1/UAF1 complex