Item – Theses Canada

​
OCLC number
748081592
Link(s) to full text
LAC copy
LAC copy
Author
Kepkay, Rosemarie B.(Rosemarie Beth),1985-
Title
The role of KRAB-ZFP associated protein 1 (KAP-1) in the control of promyelocytic leukaemia nuclear body (PML NB) number.
Degree
M. Sc. -- Dalhousie University, 2009
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2010]
Description
2 microfiches
Notes
Includes bibliographical references.
Abstract
Promyelocytic leukemia nuclear bodies (PML NBs) are dynamic subnuclear protein compartments that are thought to play roles in many diverse cellular functions. The major component of PML NBs is the PML protein, and PML gene expression is frequently lost in human cancers. PML NBs also play a role in the response to DNA damage. We and others have shown that PML NBs behave as DNA-damage sensors by increasing in number following the induction of DNA breaks. However, the molecular mechanism behind this phenomenon has not been elucidated. Previous studies have established that the ataxia telangiectasia (AT) mutated (ATM) and AT and Rad3-related (ATR) kinase pathways can regulate PML NB number post-DNA damage. After ATM activation, DNA repair is initiated as well as decondensation of chromatin by phosphorylation of KRAB-ZFP associated protein 1 (Kap1). PML NBs make contacts with the surrounding chromatin and can increase in number in response to perturbations in chromatin structure. Therefore, changes in PML NB number in response to DNA damage may arise due to ATM-mediated Kap1-dependent decondensation of chromatin. We have assessed PML NB number in normal and Kap1-deficient cells before and after DNA damage. Loss of Kap1 causes PML NB number to increase without DNA damage, directly implicating Kap1 in the control of PML NB number due to changes in chromatin structure. Phosphorylation of Kap1 also plays a role in regulating PML NB number. A Kap1-independent process regulates PML NB number following DNA damage, as PML NB number further increase post-DNA damage. Understanding the mechanism(s) behind this phenomenon is an important step towards individualized cancer therapy by validating the PML NB as a biomarker for tumour response to radiation and chemotherapy.
ISBN
9780494563144
0494563141