We have identified a Xenopus laevis protein factor that specifically recognizes vertebrate telomeric repeats at DNA ends. This factor, called Xenopus telomere end factor (XTEF), is detected predominantly in extracts of Xenopus eggs and ovaries, which are estimated to contain sufficient XTEF to bind approximately 3 x 10(7) DNA ends. In contrast, XTEF is much less abundant (approximately 90 per cell) in extracts of somatic cell nuclei. Mobility retardation analysis of the XTEF activity in egg extracts indicates that this factor binds the vertebrate telomeric repeat sequence (TTAGGG)2 when present in a single-stranded 3' overhang. Single-stranded 3' extensions of (TTTGGG)2, (AAAGGG)2, (TTACCC)2, or a nonrepetitive sequence fail to bind XTEF efficiently, whereas changes in the double-stranded sequence 5' to the TTAGGG repeat tail are tolerated. TTAGGG repeats are not recognized at internal position, at a 5' protruding end, or in double-stranded DNA. In addition, the factor does not bind RNA with single-stranded UUAGGG repeats at a 3' end. XTEF-DNA complexes form and are stable in high salt. The DNA-binding properties of XTEF resemble the characteristics of a class of terminus-specific telomere proteins identified previously in hypotrichous ciliates.
Abstract Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor) inhibits MRN at budding yeast telomeres by binding to RAD50 and evolved at least twice, in unrelated telomeric proteins Rif2 and Taz1. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for this telomeric mechanism for binding MRN, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.
The introduction of sleep endoscopy in the diagnosis of sleep apnea-hypopnea syndrome (OSAHS) has led to the development of a customization in the surgical approach of patients refusing nocturnal ventilation.Sometimes follow up polysomnography can show a recurrence of OSAHS, even in patients with no changes in weight or head and neck anatomy.We report a case of a patient undergone uvulopalatopharyngoplasty and epiglottoplasty showing a worsening of OSAHS years after surgery.A 69-year-old man with moderate OSAHS refusing overnight ventilation underwent sleep endoscopy showing collpase of palate, tongue base and epiglottis.Uvulopalatopharyngoplasty and epiglottoplasty were then perfomed in addiction to application of mandibular advancement device (MAD), with normalization of parameters, as shown by the following polysomnographies.Over time, symptomes started to recur, and the patient underwent a new polysomnpography showing increase of apnea-hypopnoea index (AHI).A second sleep endoscopy was therefore performed, pointing out the role of the collapse of the residual epiglottis in developing apneas.Epiglottis stiffening operation was consequently perfomed with resolution of symptoms and reduction of AHI.Patients treated with surgery and MAD should always be monitored with follow up polysomnography.Worsening of symptoms should be evaluated by means of sleep endoscopy in order to identify and treat the new causes of obstruction.
Telomere function is mediated by the assembly of a protein complex on an array of telomeric DNA (TG) repeats synthesized by the telomerase enzyme. Telomerase action at chromosome ends is finely tuned by the telomeric complex so that a constant average number of repeats is maintained. This is achieved through a negative feedback process that is sensitive to TG tract length, but whose underlying mechanism is unknown. We show that short telomeres, which are preferential substrates for telomerase, display increased association with the enzyme in the S phase of the cell cycle, when telomerase acts. In addition, we provide support for a molecular mechanism by which this key step of telomerase recruitment is regulated by TG tract length.
La vasculopatia polipoidale coroideale (PCV), per la prima volta descritta nel 1982, e una patologia degenerativa della retina che coinvolge primitivamente il circolo coroideale. La migliore conoscenza di questa condizione cui si e pervenuti negli ultimi anni ha permesso di valutare le diverse possibilita terapeutiche a disposizione. Questo studio si propone di andare ad indagare l’efficacia nel tempo del trattamento con Ranibizumab intravitreale in 23 occhi affetti da PCV in termini di acuita visiva (AV) e spessore foveale centrale (SFC) a 3 e 6 mesi dalla prima iniezione. I risultati sono stati messi a confronto con quelli ottenuti in un gruppo di soggetti affetti da un quadro di neovascolarizzazione coroideale (CNV) classica. Inoltre, all’interno dei pazienti con PCV sono stati creati 3 sottogruppi in base alla morfologia delle lesioni al fine di individuare eventuali fattori clinici prognostici di diversa risposta al trattamento. I risultati ottenuti sono stati positivi sia in termini di miglioramento dell’AV che di riduzione dello SFC. Il maggior recupero visivo si e visto nel primo gruppo (microaneurismi), mentre l’efficacia maggiore sullo SFC si e osservata nel secondo gruppo (polipi).
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