Project Summary/Abstract
We and others showed that ferredoxin reductase (FDXR), a mitochondrial flavoprotein, is induced by
DNA damage in a p53-dependent manner and regulates apoptosis induced by reactive oxygen species.
As the only human ferredoxin reductase, FDXR receives two electrons from NADPH and transfers them
one at a time to its cognate substrates ferredoxin 1 (FDX1) and FDX2 and subsequently, plays a role in
biogenesis of steroids and iron sulfur cluster proteins. Despite these well-defined biochemical
functions, the role of FDXR in tumor suppression is still poorly understood. Interestingly, recent studies
showed that FDXR is the most consistent acute sensor following DNA damage, suggesting that FDXR
plays a role in DNA damage response and repair. Indeed, our pilot studies showed that FDXR is also
expressed in the nucleus and regulates cell growth and survival potentially via its nuclear substrates
(p53, Mdm2, and Mdm4) in response to a stress. These observations prompt us to hypothesize that the
nuclear FDXR has a critical biological function in tumor suppression. To further test this, two specific
aims are proposed: (1) To determine how FDXR subcellular localization is regulated; (2) To determine
how the nuclear FDXR exerts its biological function.