Phosphorylation at serine 331 is required for Aurora B activation

Chk1 phosphorylates Aurora B to promote its full activation during mitotic prometaphase

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

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

First published: 16 February 202

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder

Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects

The conserved protein kinase Chk1 is believed to play an important role in checkpoint responses to aberrant DNA structures; however, genetic analysis of Chk1 functions in metazoans is complicated by lethality of Chk1-deficient embryonic cells. We have used gene targeting to eliminate Chk1 function in somatic DT40 B-lymphoma cells. We find that Chk1-deficient DT40 cells are viable, but fail to arrest in G(2)/M in response to and are hypersensitive to killing by ionizing radiation. Chk1-deficient cells also fail to maintain viable replication forks or suppress futile origin firing when DNA polymerase is inhibited, leading to incomplete genome duplication and diminished cell survival after release from replication arrest. In contrast to embryonic cells, however, Chk1 is not required to delay mitosis when DNA synthesis is inhibited. Thus, Chk1 is dispensable for normal cell division in somatic DT40 cells but is essential for DNA damage-induced G(2)/M arrest and a subset of replication checkpoint responses. Furthermore, Chk1-dependent processes promote tumour cell survival after perturbations of DNA structure or metabolism

Differential regulation of AP-1 and novel TRE-specific DNA-binding complexes during differentiation of oligodendrocyte-type-2-astrocyte (O-2A) progenitor cells

AP-1 is an ubiquitous transcription factor which is composed of the Jun and Fos proto-oncogene proteins and is thought to play a role in both cell proliferation and differentiation. We have used an immortal, bipotential oligodendrocyte-type-2 astrocyte progenitor cell line (O-2A/c-myc) which can differentiate into oligodendrocytes or type-2 astrocytes in vitro, to investigate whether AP-1 DNA-binding activity fluctuates during glial cell differentiation. Unexpectedly, DNA-mobility shift assays using a TRE-containing oligonucleotide derived from the promoter of the glial-specific gene, glial fibrillary acidic protein (GFAP/AP-1), revealed that O-2A/c-myc progenitor cells were devoid of conventional AP-1 DNA-binding complexes. O-2A/c-myc cells did however contain several novel GFAP/AP-1-specific DNA-binding complexes, which we have termed APprog. APprog complexes recognise the TRE consensus motif present in the GFAP/AP-1 oligonucleotide together with adjacent 3' sequences but do not contain c-Jun or any other known Jun-related proteins. When O-2A/c-myc cells underwent terminal differentiation APprog complexes were lost and conventional AP-1 DNA-binding activity became evident, particularly in astrocytes. These changes appear to be closely linked to the differentiation process since they did not occur in a derivative of the O-2A/c-myc cell line that contains an activated v-ras oncogene and which fails to differentiate under appropriate culture conditions. The inverse regulation of conventional AP-1 and APprog complexes within the O-2A lineage suggests that these factors may play a role in the regulation of glial cell differentiation or glial cell-specific gene expression

The secret life of histones

AbstractRecent evidence reveals an unexpected role for the linker histone H1.2 in DNA damage-induced apoptosis. DNA double strand breaks induce translocation of nuclear H1.2 to the cytoplasm, where it promotes release of cytochrome c from mitochondria by activating the Bcl-2 family protein, Bak

Chk1 is required for spindle checkpoint function

The spindle checkpoint delays anaphase onset in cells with mitotic spindle defects. Here, we show that Chk1, a component of the DNA damage and replication checkpoints, protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol, but not when microtubules are completely depolymerized by nocodazole. Spindle checkpoint failure in Chk1-deficient cells correlates with decreased Aurora-B kinase activity and impaired phosphorylation and kinetochore localization of BubR1. Furthermore, Chk1 phosphorylates Aurora-B and enhances its catalytic activity in vitro. We propose that Chk1 augments spindle checkpoint signaling and is required for optimal regulation of Aurora-B and BubR1 when kinetochores produce a weakened signal. In addition, Chk1-deficient cells exhibit increased resistance to taxol. These results suggest a mechanism through which Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling