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Fancd2 in vivo interaction network reveals a non-canonical role in mitochondrial function
Tingting Zhang1,2, Wei Du1, Andrew F Wilson1
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Abstract:
Fancd2 is a component of the Fanconi anemia (FA) DNA repair pathway, which is frequently found defective in human cancers. The full repertoire of Fancd2 functions in normal development and tumorigenesis remains to be determined. Here we developed a Flag- and hemagglutinin-tagged Fancd2 knock-in mouse strain that allowed a high throughput mass spectrometry approach to search for Fancd2-binding proteins in different mouse organs. In addition to DNA repair partners, we observed that many Fancd2-interacting proteins are mitochondrion-specific. Fancd2 localizes in the mitochondrion and associates with the nucleoid complex components Atad3 and Tufm. The Atad3-Tufm complex is disrupted in Fancd2-/- mice and those deficient for the FA core component Fanca. Fancd2 mitochondrial localization requires Atad3. Collectively, these findings provide evidence for Fancd2 as a crucial regulator of mitochondrion biosynthesis, and of a molecular link between FA and mitochondrial homeostasis.
Insights
Fanconi anemia (FA) protein Fancd2 regulates mitochondrial biosynthesis and homeostasis. This study reveals a novel link between FA DNA repair and mitochondrial function, crucial for normal development and cancer prevention.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Fanconi anemia (FA) is a DNA repair disorder linked to cancer.
- The complete functions of Fanconi anemia complementation group D2 (Fancd2) are not fully understood.
- Investigating Fancd2's roles beyond DNA repair is critical.
Purpose of the Study:
- To identify novel Fancd2-interacting proteins and functions.
- To explore Fancd2's role in normal development and tumorigenesis.
- To elucidate the connection between FA pathway and mitochondrial homeostasis.
Main Methods:
- Developed a Flag- and hemagglutinin-tagged Fancd2 knock-in mouse model.
- Employed high-throughput mass spectrometry to identify Fancd2-binding proteins.
- Utilized mouse models deficient in Fancd2 and Fanca for comparative analysis.
Main Results:
- Identified numerous mitochondrion-specific Fancd2-interacting proteins.
- Demonstrated Fancd2 mitochondrial localization and association with Atad3 and Tufm.
- Showed disruption of the Atad3-Tufm complex in Fancd2-deficient mice.
- Confirmed Atad3 is required for Fancd2 mitochondrial localization.
Conclusions:
- Fancd2 is a key regulator of mitochondrial biosynthesis.
- Established a molecular link between the Fanconi anemia pathway and mitochondrial homeostasis.
- Suggests novel therapeutic targets for FA-related cancers by modulating mitochondrial function.