The familial breast-ovarian tumor suppressor gene product BRCA1 was found to be a component of the RNA polymerase II holoenzyme by several criteria. BRCA1 was found to copurify with the holoenzyme over multiple chromatographic steps. Other tested transcription activators that could potentially contact the holoenzyme were not stably associated with the holoenzyme as determined by copurification. Antibody specific for the holoenzyme component hSRB7 specifically purifies BRCA1. Immunopurification of BRCA1 complexes also specifically purifies transcriptionally active RNA polymerase II and transcription factors TFIIF, TFIIE, and TFIIH. Moreover, a BRCA1 domain, which is deleted in about 90% of clinically relevant mutations, participates in binding to the holoenzyme complex in cells. These data are consistent with recent data identifying transcription activation domains in the BRCA1 protein and link the BRCA1 tumor suppressor protein with the transcription process as a holoenzyme-bound protein.BRCA1 is a tumor suppressor gene that is mutated in a significant fraction of cases of inherited breast and ovarian cancer. Approximately 3% of breast cancer is attributable to inherited mutations in BRCA1. Indeed, in ϳ50% of families with an abnormally high incidence of breast cancer through multiple generations, the offending mutation is in the BRCA1 gene (1-3). The BRCA1 product is likely to have tumor suppression function, since tumors arising in members of BRCA1-linked families show loss of heterozygosity at the BRCA1 locus, with retention of the mutant͞disease-predisposing allele (4, 5).The BRCA1 gene encodes a 1,863-amino acid protein without extensive homology to other proteins (1, 2). The primary sequence is noteworthy for a RING-finger motif and an acidic carboxyl terminus (1), both of which are characteristics of certain transcription factors. The BRCA1 7.8-kb mRNA is observed in many tissues, with expression highest in testis and thymus (1). About 90% of the mutations observed in the BRCA1 gene result in truncations, and the remainder of clinically relevant mutations are individual missense abnormalities that are scattered along the entire coding unit (3).A defined carboxyl-terminal segment of BRCA1 can activate transcription when fused to the DNA binding domain of GAL4 (6, 7). These fusion proteins activated transcription from promoters containing a GAL4 binding site. Importantly, fusion proteins bearing clinically relevant point mutations were inactive in this assay, implying, at a minimum, that the transcription assay is a faithful monitor of the native structure of a segment of the protein. Although there are other interpretations, these data have licensed the speculation that BRCA1 is, at least in part, a transcription factor. Whatever the significance of the transactivation potential of its carboxylterminal region, there is now evidence pointing to a role for BRCA1 in the control of DNA repair and genome stability (8). Hence, if it proves to have genuine transcription regulation function, it will be int...