Year: 2017
Type: article
Abstract: DNA damage signaling and repair pathways can intersect with andimpact cellular activity at sites far from damaged DNA, linking a cell'smetabolic state to recovery of genomic integrity. Hyperactivation of the single strand break repair (SSBR) signaling enzyme poly(ADP-ribose) polymerase-1 (PARP-1) induces consumption of the metabolite NAD+ and induction of cell death by parthanatos. Release and nuclear accumulation of mitochondrial Apoptosis-Inducing Factor (AIF) is a key event in linking PARP-1 signaling to parthanatos. We are examining allosteric switching of AIF architecture as the molecular mechanism that regulates this transition. Using small-angle x-ray scattering (SAXS), X-ray crystallography, and molecular dynamics simulations, we have defined molecular pathways linking AIF's NADH active site to sites of allostery. We are furthermore extending these insights to understand how mitochondrial sortingfactor CHCHD4 regulates higher-order oligomerization in AIF.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2779786543