Timeless Links Replication Termination to Mitotic Kinase Activation

The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim) associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1). Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication

p63 and p73 Transcriptionally Regulate Genes Involved in DNA Repair

The p53 family activates many of the same genes in response to DNA damage. Because p63 and p73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique transcriptional network. Therefore, we performed a genome-wide analysis using cells lacking the p53 family members after treatment with DNA damage. We identified over 100 genes involved in multiple pathways that were uniquely regulated by p63 or p73, and not p53. Further validation indicated that BRCA2, Rad51, and mre11 are direct transcriptional targets of p63 and p73. Additionally, cells deficient for p63 and p73 are impaired in DNA repair and p63+/−;p73+/− mice develop mammary tumors suggesting a novel mechanism whereby p63 and p73 suppress tumorigenesis

The relationship of basic need satisfaction, motivational climate and personality to well-being and stress patterns among elite athletes : An explorative study

This study investigated whether need satisfaction, need dissatisfaction, motivational climate, perfectionism and self-esteem relate to athletes’ discrete profiles of hedonic and eudaimonic well-being and perceived stress. Participants were 103 elite active orienteers (49 men and 54 women; mean age = 22.3 ± 4.4) who clustered into three distinctive well-being and stress patterns: Cluster 1 (lower well-being/higher stress; n = 26), Cluster 2 (higher well-being/lower stress; n = 39), and Cluster 3 (moderate well-being/moderate stress; n = 36). Cluster 1 and 2 constituted distinct well-being/stress profiles and differed significantly (p < .01) in mastery-oriented climate, need satisfaction, need dissatisfaction, perfectionistic concerns and self-esteem scores. A discriminant analysis showed these five variables to correctly assign 88 % of Cluster 1 and 2 participants into their respective groups, although mastery-oriented climate was revealed as a less influential indicator (function loading <.40). The substantial function loading of need dissatisfaction supports the importance of assessing both need satisfaction and dissatisfaction as they contribute uniquely to well-being

Two roles for Rad50 in telomere maintenance

We describe two roles for the Rad50 protein in telomere maintenance and the protection of chromosome ends. Using fluorescence in situ hybridisation (FISH) and fibre-FISH analyses, we show that absence of AtRad50 protein leads to rapid shortening of a subpopulation of chromosome ends and subsequently chromosome-end fusions lacking telomeric repeats. In the absence of telomerase, mutation of atrad50 has a synergistic effect on the number of chromosome end fusions. Surprisingly, this ‘deprotection' of the shortened telomeres does not result in increased exonucleolytic degradation, but in a higher proportion of anaphase bridges containing telomeric repeats in atrad50/tert plants, compared to tert mutant plants. Absence of AtRad50 thus facilitates the action of recombination on these shortened telomeres. We propose that this protective role of Rad50 protein on shortened telomeres results from its action in constraining recombination to sister chromatids and thus avoiding end-to-end interactions