The Hat1 histone acetyltransferase has been implicated in the acetylation of histone H4 during chromatin assembly. In this study, we have characterized the Hat1 complex from the fission yeast Schizosaccharomyces pombe and have examined its role in telomeric silencing. Hat1 is found associated with the RbAp46 homologue Mis16, an essential protein. The Hat1 complex acetylates lysines 5 and 12 of histone H4, the sites that are acetylated in newly synthesized H4 in a wide range of eukaryotes. Deletion of hat1 in S. pombe is itself sufficient to cause the loss of silencing at telomeres. This is in contrast to results obtained with an S. cerevisiae hat1⌬ strain, which must also carry mutations of specific acetylatable lysines in the H3 tail domain for loss of telomeric silencing to occur. Notably, deletion of hat1 from S. pombe resulted in an increase of acetylation of histone H4 in subtelomeric chromatin, concomitant with derepression of this region. A similar loss of telomeric silencing was also observed after growing cells in the presence of the deacetylase inhibitor trichostatin A. However, deleting hat1 did not cause loss of silencing at centromeres or the silent mating type locus. These results point to a direct link between Hat1, H4 acetylation, and the establishment of repressed telomeric chromatin in fission yeast. During nucleosome assembly, newly synthesized H4 is acetylated prior to its deposition onto DNA (2,40,71,83). In humans, Drosophila, and Tetrahymena, the acetylation of new H4 takes place in a conserved pattern, at lysines 5 and 12 (the sites are K4 and K11 in Tetrahymena, due to a deletion of the usual arginine residue at position 3) (24, 76). Deacetylation of new H4 occurs over the next 30 to 60 min (40, 73) and is required for proper chromatin maturation (6). The acetylation of new H4 may facilitate the import of H3/H4 dimers into the nucleus (5,15,21,26,31,87). Moreover, recent studies using Physarum as a model system have provided evidence that the K5/K12 diacetylation of H4 is required for efficient nucleosome assembly in that system (26). It therefore seems likely that the rigorous conservation of the diacetylation of nascent H4 reflects an important role in the import/ assembly process.The most likely candidate for the enzyme that acetylates newly synthesized H4 is Hat1 (Kat1), a type B histone acetyltransferase (HAT) (7, 60). Hat1 acetylates free H4 at lysines 5 and 12 in vitro, consistent with the acetylation pattern of new H4 (22,24,46,64,68,75,82). In many organisms Hat1 is associated with p46 (termed Hat2p in Saccharomyces cerevisiae), which stimulates its enzymatic activity (59, 72, 82). Although it was long thought of as predominantly a cytoplasmic enzyme, it is now clear that Hat1 is also present in nuclei (1,51,63,68,72,82). In S. cerevisiae, the nuclear Hat1 complex also contains the protein Hif1p (1, 63).Several lines of evidence have indicated that Hat1 is involved in DNA damage repair (12,14,66) and can be recruited to the sites of DNA double-strand breaks (67). Moreover, in co...
PurposeWhite light cystoscopy (WLC) is the standard procedure for visualising non-muscle invasive bladder cancer (NMIBC). However, WLC can fail to detect all cancerous lesions, and outcomes with transurethral resection of the bladder differ between institutions, controlled trials, and possibly between trials and routine application. This noninterventional study assessed the benefit of hexaminolevulinate blue light cystoscopy (HALC; Hexvix®, Ipsen Pharma GmbH, Germany) plus WLC versus WLC alone in routine use.MethodsFrom May 2013 to April 2014, 403 patients with suspected NMIBC were screened from 30 German centres to perform an unprecedented detailed assessment of the additional detection of cancer lesions with HALC versus WLC alone.ResultsAmong the histological results for 929 biopsy samples, 94.3 % were obtained from suspected cancerous lesions under either WLC or HALC: 59.5 % were carcinoma tissue and 40.5 % were non-cancerous tissue. Of all cancer lesions, 62.2 % were staged as Ta, 20.1 % as T1, 9.3 % as T2, 7.3 % as carcinoma in situ (CIS), and 1.2 % were unknown. Additional cancer lesions (+6.8 %) and CIS lesions (+25 %, p < 0.0001) were detected by HALC plus WLC versus WLC alone. In 10.0 % of patients, ≥1 additional positive lesion was detected with HALC, and 2.2 % of NMIBC patients would have been missed with WLC alone. No adverse events were observed.ConclusionsThe results of this study demonstrate that HALC significantly improves the detection of NMIBC versus WLC alone in routine clinical practice in Germany. While this benefit is statistically significant across all types of NMIBC, it seems most relevant in CIS.
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