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Published on: January 31, 2019
Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A
Marie-Ming Aynaud1, Rodolphe Suspène, Pierre-Olivier Vidalain
1Molecular Retrovirology Unit, CNRS URA3015, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris cedex 15, France.
Insights
Tribbles 3 (TRIB3) interacts with APOBEC3A/C DNA mutators, repressing their nuclear activity and preventing DNA damage. This interaction links these mutators to cancer pathways, highlighting TRIB3's role in genome integrity.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Human cytidine deaminases APOBEC3A, APOBEC3C, and APOBEC3H are nuclear DNA mutators.
- APOBEC3A alone efficiently edits nuclear DNA, leading to uracil excision and potential double-stranded breaks.
Purpose of the Study:
- To identify protein networks associated with APOBEC3A and APOBEC3C DNA mutators.
- To elucidate the regulatory role of TRIB3 in nuclear DNA editing and genome integrity.
Main Methods:
- Yeast two-hybrid screen to identify protein interactors.
- Co-affinity purification to confirm interactions.
- Co-transfection and siRNA knockdown experiments to assess functional impact.
Main Results:
- TRIB3 was identified as an interactor of APOBEC3A and APOBEC3C.
- TRIB3 repressed nuclear DNA editing by APOBEC3A and associated double-stranded breaks.
- TRIB3 interaction led to proteasome-independent degradation of APOBEC3A.
- TRIB3 links APOBEC3A/C to the Rb-BRCA1-ATM network.
Conclusions:
- TRIB3 acts as a repressor of APOBEC3A nuclear DNA editing.
- TRIB3 plays a crucial role in maintaining genome integrity by regulating DNA mutators.
- TRIB3 connects DNA mutators to cancer-related pathways, suggesting its significance in oncogenesis.
Abstract:
The human polydeoxynucleotide cytidine deaminases APOBEC3A, APOBEC3C, and APOBEC3H are capable of mutating viral DNA in the nucleus, whereas APOBEC3A alone efficiently edits nuclear DNA. Deamination is rapidly followed by excision of uracil residues and can lead to double-stranded breaks. It is not known to which protein networks these DNA mutators belong. Using a yeast two-hybrid screen, we identified the human homolog of Drosophila Tribbles 3, TRIB3, as an interactor for APOBEC3A and APOBEC3C. The interaction was confirmed by co-affinity purification. Co-transfection of APOBEC3A with a TRIB3 expression vector reduced nuclear DNA editing whereas siRNA knockdown of TRIB3 increased the levels of nuclear DNA editing, indicating that TRIB3 functioned as a repressor of A3A. It also repressed A3A-associated γH2AX positive double-stranded breaks. The interaction results in degradation of A3A in a proteasome-independent manner. TRIB3 has been linked to cancer and via its own interactors and links the A3A DNA mutators to the Rb-BRCA1-ATM network. TRIB3 emerges as an important guardian of genome integrity.
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