Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.564540
Title: Cell cycle-dependent modification of Pot1 and its effects on telomere function
Author: Kuznetsov, V.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2009
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
Telomere functions are tightly controlled throughout the cell cycle to allow telomerase access while suppressing a bona fide DNA damage response (DDR) at linear chromosome ends. However, the mechanisms that link cell cycle progression with telomere functions are largely unknown. Here we show that a key S-phase kinase, DDK (Dbf4-dependent protein kinase), phosphorylates the telomere binding protein Pot1, and that this phosphorylation is crucial for DNA damage checkpoint inactivation, the suppression of homologous recombination (HR) at telomeres, and the prevention of telomere loss. DDK phosphorylates Pot1 in a very conserved region of its most amino-terminal-proximal OB fold, suggesting that this regulation of telomere function may be widely conserved. Mutation of Pot1 phosphorylation sites leads to telomerase independent telomere maintenance through constant HR, as well as a dependence of telomere maintenance proteins involved in checkpoint activation and HR. These results uncover a novel and important link between DDR suppression and telomere maintenance. The failure in Pot1 phosphorylation and DDR inactivation could potentially lead to uncontrolled cell proliferation without a requirement for telomerase by switching cells to HR dependent telomere homeostasis. In mammals this could result in ALT (Alternative Lengthening of Telomeres), a recombination dependent mode of telomere maintenance, uncontrolled cell proliferation and cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.564540  DOI: Not available
Share: