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Unraveling Novel Functions of SIR Complex in Heterochromatic Silencing
Başlık:
Unraveling Novel Functions of SIR Complex in Heterochromatic Silencing
Yazar:
Zukowski, Alexis Min, author.
ISBN:
9780438003019
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (159 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Aaron M. Johnson; Michael McMurray Committee members: Joshua Black; Mair Churchill; Robert Sclafani; Deborah Wuttke.
Özet:
Cell differentiation requires regulated alterations in chromatin structure that result in changes in transcriptional activity and replication timing of the genome. Heterochromatin is a highly condensed and hypoacetylated domain that represses gene transcription and replication initiation. The sirtuin heterochromatin system in budding yeast is mediated by the SIR complex and represents a tractable and streamlined model system of heterochromatin. The SIR complex is a histone deacetylase (HDAC) complex that acts at the telomeres and at the silent mating-type loci, HMR and HML. The HDAC activity possessed by SIR complex is insufficient to transition an active region into a repressed one and must recruit other factors. We identified a new step in the heterochromatin assembly pathway that involves the recruitment and allosteric stimulation of a histone deubiquitinase, Ubp10. Mono-ubiquitinated histone H2B (H2B-Ub) is required for the catalysis of active H3 methylation marks, H3K4me3 and H3K79me3. These marks oppose SIR complex binding and spreading. Ubp10 targets H2B-Ub in vivo, thus we used unique H2B-Ub substrates to characterize Ubp10 activity. We show that Sir2/4 directly interacts with Ubp10, targets Ubp10 to chromatin and enhances Ubp10 DUB activity on H2B-Ub nucleosomes. We propose that this is important a SIR complex-mediated transition of an active region to a silent one. In a separate study, we wanted to determine the chromatin-specific requirements that regulate the temporal activation of replication origins, specifically repressed heterochromatic origins. It is well conserved that the timing of heterochromatin replication occurs later in S-phase than euchromatin. Yet at heterochromatic loci, all origins have loaded MCMs and undergo activation only when S-phase is chemically slowed. Using a novel heterochromatin-based in vitro replication system, my preliminary data indicates that heterochromatin structure interferes with a downstream assembly step, the formation of the Cdc45-MCM-GINS (CMG) complex at the origin. This is a potential mechanism by which heterochromatin dictates origin initiation and contributes to late replication in S-phase. Our findings demonstrate new functions for SIR complex in heterochromatin assembly and in the regulation of DNA replication at heterochromatic origins.
Notlar:
School code: 1639
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680314.1) | 680314-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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