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Title: The role of Tel1 at short telomeres
Author: Sridhar, Akila
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2013
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DNA replication is initiated at replication origins, which are temporally regulated within the S phase of the cell cycle so that some origins initiate early, while others initiate late. S. cerevisiae telomeres of normal length replicate late during the S phase. However, shortened telomeres replicate early – coupling the regulation of length to the replication timing. The mechanism through which telomere length regulates the activation time of nearby replication origins is unknown. In this thesis, I find that Tel1, a homolog of human ATM kinase, is required for early replication of short telomeres. In the absence of Tel1, short telomeres of the yku70Δ mutant no longer replicate early. I tested the role of Histone H2A(X) phosphorylation at Serine-129, as the target of Tel1 kinase, in regulation of telomeric replication times. However, preventing this phosphorylation had only a minor effect, so H2A(X) is unlikely to be the sole Tel1 target in telomeric replication regulation. On the other hand, deletion of Rif1 – a telomeric length regulator – showed complete epistasis to tel1Δ in telomeric replication regulation, implying that Rif1 acts downstream of Tel1 in the regulation of telomeric replication. Proteomic analysis revealed Tel1-dependent phosphorylation of Rif1 upon telomere shortening, implicating Rif1 as a direct downstream target of Tel1. However, mutation of the Tel1-phosphorylation sites on Rif1 had only a small effect on telomere replication times, indicating that phosphorylation of Rif1 by Tel1 is not the sole mechanism governing replication timing of short telomeres.
Supervisor: Not available Sponsor: Cancer Research UK ; Overseas Research Students Awards Scheme
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: DNA replication ; Telomerization ; Saccharomyces cerevisiae