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The interaction of CtIP with DNA damage response proteins

Abramowicz, Iga Agnieszka (2010)
Ph.D. thesis, University of Birmingham.

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Abstract

In the course of this study it was established that CtlP associates in vivo with, and directly binds to, the DNA damage mediator proteins containing BRCT domains: 53BP1, MDC1, TopBP1 and NBS1. The binding sites on all of these proteins have been mapped establishing which regions of CtlP interact directly with 53BP1, MDC1, TopBP1 and NBS1 and vice versa. This implies that CtlP is involved in the DNA damage response on many levels interacting with proteins that mediate different aspects of DNA damage sensing and signalling. CtIP's nuclear localization before and after DNA damage was determined and its colocalization with the other DNA damaged responsive proteins examined. It was found that CtIP associates in vivo with DNA damage sensor proteins such as the MRN complex (Mre11, Rad50 and NBS1) and RPA70, signal transducer proteins such as the PIKK kinases ATM, ATR and SMG1 and the mediator proteins 53BP1 and MDC1. All of those proteins are involved in detecting and repairing double stranded or single stranded lesions. Moreover CtIP has a major influence on phosphorylation events induced during repair processes and thus could be an inducer of kinase activity. The deletion of CtlP causes impairment of phosphorylation of important proteins that take part in the DNA damage response pathways such as NBS1, ATM, 53BP1, Chk1 and RPA70. However, impaired phosphorylation only occurs in response to single stranded DNA lesions or the collapse of replication forks. This implies that it is the ATR pathway that is malfunctioning in CtIP depleted cells. CtIP was previously reported to be phosphorylated on Ser664 and Ser745 by the ATM kinase in response to the DNA double stranded breaks. I have established two possible new phosphorylation sites: Ser506 and Ser555. They could be potentially involved in CtlP's redistribution to the DNA damage sites but this remains to be elucidated.

Type of Work:Ph.D. thesis.
Supervisor(s):Grand, Roger and Turnell, Andrew
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute of Cancer Studies
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:959
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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