Graduation Year

2011

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Alvaro Monteiro

Keywords

Breast cancer, DNA damage response, DNA-PKcs, Filamin A, Varints of Uncertain Signifficance

Abstract

ABSTRACT

Individuals that carry deleterious mutations in the breast and ovarian cancer susceptibility gene 1 (BRCA1) have much more elevated risk to develop breast and/or ovarian cancer than the individuals from the general population. The BRCA1 gene product has been implicated in several aspects of the DNA damage response, but its biochemical function in these processes has remained elusive. In order to probe BRCA1 functions we conducted a yeast two-hybrid screening to identify interacting partners to a conserved motif (Motif 6) in the central region of BRCA1. In this dissertation, we report the identification of the actin-binding protein Filamin A (FLNA) as a BRCA1 partner and demonstrate that FLNA is required for the efficient regulation of DNA repair process at its early stages. Cells lacking FLNA display a diminished ionizing radiation (IR)-induced BRCA1 focus formation and a slow kinetics of Rad51 focus formation. In addition, our data demonstrate that FLNA is required to stabilize the interaction between DNA-PK holoenzyme components such as DNA-PKcs and Ku86 in a BRCA1-independent manner. Our data are consistent with a model in which the absence of FLNA compromises homologous recombination and non-homologous end joining. Our findings have implications for our understanding of the response to irradiation-induced DNA damage.

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