؉ , but the overhang reappeared following concomitant deletion of pku70 ؉ . Our data suggest that the Rad50 complex can process DSB ends and telomere ends in the presence of the Ku heterodimer. However, the Ku heterodimer inhibits processing of DSB ends and telomere ends by alternative nucleases in the absence of the Rad50-Rad32 protein complex. While we have identified Exo1 as the alternative nuclease targeting DNA break sites, the identity of the nuclease acting on the telomere ends remains elusive.
Telomeres recruit telomerase and differentiate chromosome ends from sites of DNA damage. Although the DNA damage checkpoint PI3-kinases ATM and ATR localize to telomeres and promote telomerase activation, activation of their downstream checkpoint pathway targets is inhibited. Here, we show that the fission yeast telomeric protein Ccq1 is required for telomerase recruitment and inhibition of ATR target activation at telomeres. The loss of Ccq1 results in progressive telomere shortening and persistent ATR-dependent activation of Chk1. Unlike the checkpoint activation that follows loss of telomerase, this checkpoint activation occurs prior to detectable levels of critically short telomeres. When ccq1⌬ telomeres do become critically short, activated Chk1 promotes an unusual homologous recombination-based telomere maintenance process. We find that the previously reported meiotic segregation defects of cells lacking Ccq1 stem from its role in telomere maintenance rather than from a role in formation of the meiotic bouquet. These findings demonstrate the existence of a novel telomerase recruitment factor that also serves to suppress local checkpoint activation.[Keywords: Telomere; telomerase; DNA damage checkpoint; homologous recombination; mitosis; meiosis] Supplemental material is available at http://www.genesdev.org.
Bouquet formation, in which telomeres gather to a small region of the nuclear membrane in early meiosis, has been observed in diverse eukaryotes, but the function of the bouquet has remained a mystery. Here, we demonstrate that the telomere bouquet plays a crucial role in controlling the behavior of the fission yeast microtubule-organizing center (known as the spindle pole body or SPB) and the meiotic spindle. Using mutations that specifically disrupt the bouquet, we analyze chromosome, SPB, and spindle dynamics throughout meiosis. If the bouquet fails to form, the SPB becomes fragmented at meiosis I, leading to monopolar, multiple, and mislocalized spindles. Correct SPB and spindle behavior require not only the SPB recruitment of telomere proteins but also that the proteins are properly bound to telomeric DNA. This discovery illuminates an unanticipated level of communication between chromosomes and the spindle apparatus that may be widely conserved among eukaryotes.
AimsThe clinical course including the outcome of acute decompensated heart failure (ADHF) correlates with renal dysfunction, but the evaluation of renal function has not yet been standardized. We therefore investigated the relationship between the prognosis of ADHF and acute kidney injury (AKI) evaluated using the risk, injury, failure, loss, end stage (RIFLE) criteria. Methods and resultsThis study assessed 376 consecutive patients with ADHF admitted to the intensive care unit (ICU) (mean age 71.6 years; 238 male). The underlying aetiology was ischaemic heart disease, hypertensive heart disease, cardiomyopathy, valvular diseases, and 'other' in 124, 70, 60, 107, and 15 patients, respectively. We defined AKI according to the RIFLE criteria, and the most severe RIFLE classifications during hospitalization were adopted to assess patient outcomes. The in-hospital mortality was significantly higher among patients with AKI (29 of 275; 10.5%) than in those without AKI (1 of 101; 1.0%, P ¼ 0.0010). Both ICU and hospital stays were longer for patients with AKI (8.8 + 15.4 vs. 48.6 + 47.6 days), than for patients without (5.0 + 2.8 vs. 25.7 + 16.8 days, P , 0.05 and P , 0.001). ConclusionAcute kidney injury evaluated by the RIFLE criteria was associated with a poorer outcome for patients with ADHF.--
Understanding the intricacies of telomerase regulation is crucial due to the potential health benefits of modifying its activity. Telomerase is composed of an RNA component and reverse transcriptase. However, additional factors required during biogenesis vary between species. Here we have identified fission yeast Lar7 as a member of the conserved LARP7 family, which includes the Tetrahymena telomerase-binding protein p65 and human LARP7. We show that Lar7 has conserved RNA-recognition motifs, which bind telomerase RNA to protect it from exosomal degradation. In addition, Lar7 is required to stabilise the association of telomerase RNA with the protective complex LSm2–8, and telomerase reverse transcriptase. Lar7 remains a component of the mature telomerase complex and is required for telomerase localisation to the telomere. Collectively, we demonstrate that Lar7 is a crucial player in fission yeast telomerase biogenesis, similarly to p65 in Tetrahymena, and highlight the LARP7 family as a conserved factor in telomere maintenance.
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