The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression.
The mRNA polyadenylation factor CstF interacts with the BRCA1-associated protein BARD1, and this interaction represses the nuclear mRNA polyadenylation machinery in vitro. Given the suspected role of BRCA1/BARD1 in DNA repair, we tested whether inhibition of mRNA processing is linked to DNA damage. Strikingly, we found that 3' cleavage in extracts from cells treated with hydroxyurea or ultraviolet light was strongly, but transiently, inhibited. Although no changes were detected in CstF, BARD1, and BRCA1 protein levels, increased amounts of a CstF/BARD1/BRCA1 complex were detected. Supporting the physiological significance of these results, a previously identified tumor-associated germline mutation in BARD1 (Gln564His) reduced binding to CstF and abrogated inhibition of polyadenylation. Together these results indicate a link between mRNA 3' processing and DNA repair and tumor suppression.
Kleiman
F E
FE
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Manley
J L
JL
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D018095:Germ-Line Mutation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D039221:mRNA Cleavage and Polyadenylation Factors
D002352:Carrier Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D039221:mRNA Cleavage and Polyadenylation Factors; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases