BRCA1 can modulate RNA polymerase II carboxy-terminal domain phosphorylation levels.
A high incidence of breast and ovarian cancers has been linked to mutations in the BRCA1 gene. BRCA1 has been shown to be involved in both positive and negative regulation of gene activity as well as in numerous other processes such as DNA repair and cell cycle regulation. Since modulation of the RNA polymerase II carboxy-terminal domain (CTD) phosphorylation levels could constitute an interface to all these functions, we wanted to directly test the possibility that BRCA1 might regulate the phosphorylation state of the CTD. We have shown that the BRCA1 C-terminal region can negatively modulate phosphorylation levels of the RNA polymerase II CTD by the Cdk-activating kinase (CAK) in vitro. Interestingly, the BRCA1 C-terminal region can directly interact with CAK and inhibit CAK activity by competing with ATP. Finally, we demonstrated that full-length BRCA1 can inhibit CTD phosphorylation when introduced in the BRCA1(-/-) HCC1937 cell line. Our results suggest that BRCA1 could play its ascribed roles, at least in part, by modulating CTD kinase components.
Centre de recherche sur les mécanismes du fonctionnement cellulaire, Département de biologie, Faculté des sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1K 2R1.
Annie
A
Moisan
Chantal
C
Larochelle
Benoît
B
Guillemette
Luc
L
Gaudreau
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D056748:Cyclin H; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D019473:Transcription Factors, TFII / Q000235:genetics / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D019313:BRCA1 Protein; C534751:CCNH protein, human; D056748:Cyclin H; D016213:Cyclins; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase