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Abstract Background Family history of suicide attempt is one of the risks of suicide. We aimed at exploring the characteristics of Japanese suicide attempters with and without a family history of suicide attempt. Methods Suicide attempters admitted to an urban emergency department from 2003 to 2008 were interviewed by two attending psychiatrists on items concerning family history of suicide attempt and other sociodemographic and clinical information. Subjects were divided into two groups based on the presence or absence of a family history of suicide attempt, and differences between the two groups were subsequently analyzed. Results Out of the 469 suicide attempters, 70 (14.9%) had a family history of suicide attempt. A significantly higher rate of suicide motive connected with family relations (odds ratio 2.21, confidence interval 1.18–4.17, p < .05) as well as a significantly higher rate of deliberate self-harm (odds ratio 2.51, confidence interval 1.38–4.57, p < .05) were observed in patients with a family history of suicide compared to those without such history. No significant differences were observed in other items investigated. Conclusion The present study has revealed the characteristics of suicide attempters with a family history of suicide attempt. Further understanding of the situation of such individuals is expected to lead to better treatment provision and outcomes, and family function might be a suitable focus in their treatment.

The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient-rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19Arf, an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19Arf at Ser75. Phosphorylated p19Arf was then recognized by the F-box protein β-TrCP2 and degraded by the proteasome. Ablation of β-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19Arf. The β-TrCP2 paralog β-TrCP1 had no effect on p19Arf stability, suggesting that phosphorylated p19Arf is a specific substrate of β-TrCP2. Mice deficient in β-TrCP2 manifested accumulation of p19Arf in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via β-TrCP2-dependent p19Arf degradation under nutrient-rich conditions. [ABSTRACT FROM AUTHOR]

The histone chaperone complex FACT comprises SPT16 and SSRP1 and contributes to DNA replication, transcription, and repair, but how it plays such various roles is unclear. Here, we show that human SPT16 is ubiquitylated at lysine-674 (K674) by the DCAF14-CRL4 ubiquitin ligase. K674 is located in the middle domain of SPT16, and the corresponding residue of the yeast ortholog is critical for binding to histone H3.1-H4. We show that the middle domain of human SPT16 binds to histone H3.1-H4 and that this binding is inhibited by K674 ubiquitylation. Cells with heterozygous knockin of a K674R mutant of SPT16 manifest reduction of both SPT16 ubiquitylation and H3.1 in chromatin, a reduced population in mid S phase, impaired proliferation, and increased susceptibility to S phase stress. Our data thus indicate that SPT16 ubiquitylation by DCAF14-CRL4 regulates FACT binding to histones and may thereby control DNA replication-coupled histone incorporation into chromatin. [Display omitted] • The SPT16 subunit of the FACT complex is ubiquitylated at K674 • The ubiquitin ligase DCAF14-CRL4 is responsible for SPT16 ubiquitylation • Ubiquitylation of SPT16 inhibits its binding to histone H3.1 • SPT16 ubiquitylation increases the level of H3.1 in chromatin during S phase The histone chaperone FACT plays a role in DNA replication, transcription, and repair, but its regulation is unclear. Nakagawa et al. report that DCAF14-CRL4 ubiquitylates the FACT subunit SPT16 and that such ubiquitylation may regulate DNA replication-coupled histone incorporation into chromatin and thereby ensure efficient S-phase progression. [ABSTRACT FROM AUTHOR]

Background: Some reports have suggested the involvement of the D2 dopaminergic function in the expression of suicidal behavior. Here, we examined associations between suicide attempts and two kinds of functional polymorphisms in the dopamine D2 receptor (DRD2) gene, namely, TaqIA and –141C Ins/Del. Methods: Subjects included 120 suicide attempters and 123 unrelated volunteers. Those who attempted suicide were severely injured and were transferred to the emergency unit in our university hospital. To determine each genotype, we performed polymerase chain reaction and restriction fragment length polymorphism analyses. Results: We found significant differences in genotypic and allelic frequencies of –141C Ins/Del and TaqIA polymorphisms between suicide attempters and healthy controls (–141C Ins/Del, p = 0.01; TaqIA,p = 0.036). The Ins allele of –141C Ins/Del was significantly more frequent in suicide attempters (p = 0.011), as well as the A2 allele of TaqIA (p = 0.017). Haplotype analysis revealed no significant linkage disequilibrium between –141C Ins/Del and TaqIA polymorphisms (D′ = 0.226, r2 = 0.016, p = 0.10). Conclusions: These findings suggest that DRD2 gene polymorphisms may be involved in the biological susceptibility to suicide. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A response by Makiko Nakagawa and Chiaki Kawanishi to a letter to the editor about his article on suicide attempters who were given crisis intervention during hospital stay: published in the previous issue is presented.

Summary DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading to eventual demethylation. Inactivation of TET enzymes causes multistage developmental defects, impaired cell reprogramming, and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4 VprBP ) on a highly conserved lysine residue. Deletion of VprBP in oocytes abrogated paternal DNA hydroxymethylation in zygotes. VprBP-mediated monoubiquitylation promotes TET binding to chromatin. Multiple recurrent TET2-inactivating mutations derived from leukemia target either the monoubiquitylation site (K1299) or residues essential for VprBP binding. Cumulatively, our data demonstrate that CRL4 VprBP is a critical regulator of TET dioxygenases during development and in tumor suppression. [ABSTRACT FROM AUTHOR]

Recognition of gene promoters by RNA polymerase II is mediated by general transcription factor IID (TFIID), which has been thought to be a static complex and to play a passive role in the regulation of gene expression under the instruction of gene-specific transcription factors. Here we show that transforming growth factor β (TGF-β) induced degradation of the TFIID subunit TAF7 in cultured mouse mammary epithelial cells and that this effect was required for proliferative arrest in response to TGF-β stimulation. TGF-β stimulated transcription of the gene for the ubiquitin ligase TRIM26, which was shown to ubiquitylate TAF7 and thereby to target it for proteasomal degradation. Sustained exposure of cells to TGF-β resulted in recovery from proliferative arrest in association with amplification of the Myc proto-oncogene, with MYC inhibiting TRIM26 induction by TGF-β. Our data thus show that TFIID is not simply a general mediator of transcription but contributes to the regulation of transcription in response to cell stimulation, playing a key role in the cytostatic function of TGF-β., (Copyright © 2018 American Society for Microbiology.)

The mitosis-meiosis transition is essential for spermatogenesis. Specific and timely downregulation of the transcription factor DMRT1, and consequent induction of Stra8 expression, is required for this process in mammals, but the molecular mechanism has remained unclear. Here, we show that β-TrCP, the substrate recognition component of an E3 ubiquitin ligase complex, targets DMRT1 for degradation and thereby controls the mitosis-meiosis transition in mouse male germ cells. Conditional inactivation of β-TrCP2 in male germ cells of β-TrCP1 knockout mice resulted in sterility due to a lack of mature sperm. The β-TrCP-deficient male germ cells did not enter meiosis, but instead underwent apoptosis. The induction of Stra8 expression was also attenuated in association with the accumulation of DMRT1 at the Stra8 promoter in β-TrCP-deficient testes. DMRT1 contains a consensus β-TrCP degron sequence that was found to bind β-TrCP. Overexpression of β-TrCP induced the ubiquitylation and degradation of DMRT1. Heterozygous deletion of Dmrt1 in β-TrCP-deficient spermatogonia increased meiotic cells with a concomitant reduction of apoptosis. Collectively, our data indicate that β-TrCP regulates the transition from mitosis to meiosis in male germ cells by targeting DMRT1 for degradation., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

The kinase mTOR (mammalian target of rapamycin) promotes translation as well as cell survival and proliferation under nutrient-rich conditions. Whereas mTOR activates translation through ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP), how it facilitates cell proliferation has remained unclear. We have now identified p19(Arf), an inhibitor of cell cycle progression, as a novel substrate of S6K that is targeted to promote cell proliferation. Serum stimulation induced activation of the mTOR-S6K axis and consequent phosphorylation of p19(Arf) at Ser(75). Phosphorylated p19(Arf) was then recognized by the F-box protein β-TrCP2 and degraded by the proteasome. Ablation of β-TrCP2 thus led to the arrest of cell proliferation as a result of the stabilization and accumulation of p19(Arf). The β-TrCP2 paralog β-TrCP1 had no effect on p19(Arf) stability, suggesting that phosphorylated p19(Arf) is a specific substrate of β-TrCP2. Mice deficient in β-TrCP2 manifested accumulation of p19(Arf) in the yolk sac and died in utero. Our results suggest that the mTOR pathway promotes cell proliferation via β-TrCP2-dependent p19(Arf) degradation under nutrient-rich conditions., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Some reports have suggested the involvement of the D2 dopaminergic function in the expression of suicidal behavior. Here, we examined associations between suicide attempts and two kinds of functional polymorphisms in the dopamine D2 receptor (DRD2) gene, namely, TaqIA and -141C Ins/Del., Methods: Subjects included 120 suicide attempters and 123 unrelated volunteers. Those who attempted suicide were severely injured and were transferred to the emergency unit in our university hospital. To determine each genotype, we performed polymerase chain reaction and restriction fragment length polymorphism analyses., Results: We found significant differences in genotypic and allelic frequencies of -141C Ins/Del and TaqIA polymorphisms between suicide attempters and healthy controls (-141C Ins/Del, p = 0.01; TaqIA,p = 0.036). The Ins allele of -141C Ins/Del was significantly more frequent in suicide attempters (p = 0.011), as well as the A2 allele of TaqIA (p = 0.017). Haplotype analysis revealed no significant linkage disequilibrium between -141C Ins/Del and TaqIA polymorphisms (D' = 0.226, r(2) = 0.016, p = 0.10)., Conclusions: These findings suggest that DRD2 gene polymorphisms may be involved in the biological susceptibility to suicide., (2009 S. Karger AG, Basel.)