7 research outputs found
Tel1ATM dictates the replication timing of short yeast telomeres
Telomerase action is temporally linked to DNA replication. Although yeast telomeres are normally late replicating, telomere shortening leads to early firing of subtelomeric DNA replication origins. We show that doubleâstrand breaks flanked by short telomeric arrays cause origin firing early in S phase at lateâreplicating loci and that this effect on origin firing time is dependent on the Tel1ATM checkpoint kinase. The effect of Tel1ATM on telomere replication timing extends to endogenous telomeres and is stronger than that elicited by Rif1 loss. These results establish that Tel1ATM specifies not only the extent but also the timing of telomerase recruitment
Tpz1TPP1 SUMOylation reveals evolutionary conservation of SUMO-dependent Stn1 telomere association
Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang-binding Cdc13 is increased by Cdc13
SUMOylation. Human and fission yeast CST instead interact with overhang-binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association,and a SUMO-Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation
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Landscape review of interdisciplinary research in the UK
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Mid-term program evaluation of the joint Canada-Israel health research program (JCIHRP)
Currently in its first phase (2015-22), the program awards grants for international collaborative health research involving researchers from Canada, Israel and low- and middle-income countries (LMICs). The aim is to advance research and discovery in the field of biomedical science; to encourage scientific collaboration between researchers and trainees in Canada and Israel; and to build capacity in LMICs by fostering scientific relations and collaborations between researchers and trainees. The survey and interviews indicate some expected outcomes and benefits are emerging: advances in scientific knowledge; development of technical skills; strengthened international partnerships; and expansion of professional network
HacA-Independent Induction of Chaperone-Encoding Gene bipA in Aspergillus niger Strains Overproducing Membrane Proteins
Transcription of two unfolded protein response genes, hacA and bipA, was examined in Aspergillus niger strains overproducing membrane proteins. Despite elevated bipA mRNA levels, no 5âČ-truncated hacA transcript was detected, raising the possibility of a hacA-independent induction of bipA mRNA under the stress of membrane protein overproduction in A. niger
Break-Induced Loss of Heterozygosity in Fission Yeast: Dual Roles for Homologous Recombination in Promoting Translocations and Preventing De Novo Telomere Additionâż â
Loss of heterozygosity (LOH), a causal event in tumorigenesis, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms leading to such extensive LOH are poorly understood. We investigated the mechanisms of DNA double-strand break (DSB)-induced extensive LOH by screening for auxotrophic marker loss âŒ25 kb distal to an HO endonuclease break site within a nonessential minichromosome in Schizosaccharomyces pombe. Extensive break-induced LOH was infrequent, resulting from large translocations through both allelic crossovers and break-induced replication. These events required the homologous recombination (HR) genes rad32+, rad50+, nbs1+, rhp51+, rad22+, rhp55+, rhp54+, and mus81+. Surprisingly, LOH was still observed in HR mutants, which resulted predominantly from de novo telomere addition at the break site. De novo telomere addition was most frequently observed in rad22Î and rhp55Î backgrounds, which disrupt HR following end resection. Further, levels of de novo telomere addition, while increased in ku70Î rhp55Î strains, were reduced in exo1Î rhp55Î and an rhp55Î strain overexpressing rhp51. These findings support a model in which HR prevents de novo telomere addition at DSBs by competing for resected ends. Together, these results suggest that the mechanisms of break-induced LOH may be predicted from the functional status of the HR machinery
Failed gene conversion leads to extensive end processing and chromosomal rearrangements in fission yeast
Loss of heterozygosity (LOH), a causal event in cancer and human genetic diseases, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms by which such extensive LOH arises, and how it is suppressed in normal cells is poorly understood. We have developed a genetic system to investigate the mechanisms of DNA double-strand break (DSB)-induced extensive LOH, and its suppression, using a non-essential minichromosome, Ch16, in fission yeast. We find extensive LOH to arise from a new break-induced mechanism of isochromosome formation. Our data support a model in which Rqh1 and Exo1-dependent end processing from an unrepaired DSB leads to removal of the broken chromosome arm and to break-induced replication of the intact arm from the centromere, a considerable distance from the initial lesion. This process also promotes genome-wide copy number variation. A genetic screen revealed Rhp51, Rhp55, Rhp57 and the MRN complex to suppress both isochromosome formation and chromosome loss, in accordance with these events resulting from extensive end processing associated with failed homologous recombination repair