Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity.
The tumor suppressor protein BARD1 plays a dual role in response to genotoxic stress: DNA repair as a BARD1-BRCA1 heterodimer and induction of apoptosis in a BRCA1-independent manner. We have constructed a series of BARD1 deletion mutants and analysed their cellular distribution and capacity to induce apoptosis. As opposed to previous studies suggesting an exclusively nuclear localization of BARD1, we found, both in tissues and cell cultures, nuclear and cytoplasmic localization of BARD1. Enhanced cytoplasmic localization of BARD1, as well as appearance of a 67 kDa C-terminal proteolytic cleavage product, coincided with apoptosis. BARD1 translocates to the nucleus independently of BRCA1. For recruitment to nuclear dots, however, the BRCA1-interacting RING finger domain is required but not sufficient. Protein levels of N-terminal RING finger deletion mutants were much higher than those of full-length BARD1, despite comparable mRNA levels, suggesting that the N-terminal region comprising the RING finger is important for BARD1 degradation. Sequences required for apoptosis induction were mapped between the ankyrin repeats and the BRCT domains coinciding with two known cancer-associated missense mutations. We suggest that nuclear and cytoplasmic localization of BARD1 reflect its dual function and that the increased cytoplasmic localization of BARD1 is associated with apoptosis.
Jefford
Charles Edward
CE
Biology of Aging Laboratory, Department of Geriatrics, University of Geneva, 1225 Geneva, Switzerland.
Feki
Anis
A
Harb
Jean
J
Krause
Karl-Heinz
KH
Irminger-Finger
Irmgard
I
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D051379:Mice; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases