Regulation and Function of the Fanconi Anemia Pathway for Genome Maintenance

Author:
Collins, Natalie Bucheimer, Department of Microbiology, University of Virginia
Advisor:
Kupfer, Gary, Department of Microbiology, University of Virginia
Abstract:

Fanconi anemia (FA) is an inherited disease characterized by a variety of congenital defects, aplastic anemia, and a predisposition to cancer. On a cellular level, cells from FA patients display hypersensitivity to DNA crosslinking agents and an increased level of chromosomal rearrangements, making FA a disease of genome instability. As genome instability is a hallmark of most malignancies, FA offers a unique and valuable system in which to study human carcinogenesis. At least 13 genes and their corresponding protein products cooperate in the FA pathway, and mutation of any of these genes results in a similar phenotype. Research on FA has been limited by the fact that few of the genes involved have homologues in lower eukaryotes and few of the proteins contain conserved motifs suggestive of function. As such, FA represents a mechanism of genome maintenance restricted to higher eukaryotes. The ultimate goal of this work was to determine the function of the FA pathway by identifying other interacting proteins with known or discernable function and by determining pathways by which the FA pathway is regulated. We demonstrate that FANCA, a member of the FA pathway, is phosphorylated in response to DNA damage, that this phosphorylation is critical to the function of the pathway, and that this phosphorylation is dependent on ATR kinase, an important kinase in the cellular DNA damage response. Furthermore, we establish an interaction between the FA pathway, RNA transcription, and RNA Polymerase II, an interaction suggestive of a previously unknown function for the FA pathway and a new facet of the DNA damage response. This places FA within the context of the overall cellular response to DNA damage and defines a novel mechanism for human genome maintenance.

Note: Abstract extracted from PDF text

Degree:
PHD (Doctor of Philosophy)
Language:
English
Rights:
All rights reserved (no additional license for public reuse)
Issued Date:
2008/01/01