BRCA1-BARD1 regulates transcription through modulating topoisomerase IIβ
Heeyoun Bunch,
Jaehyeon Jeong,
Keunsoo Kang,
Doo Sin Jo,
Anh T. Q. Cong,
Deukyeong Kim,
Donguk Kim,
Dong-Hyung Cho,
You Mie Lee,
Benjamin P. C. Chen,
Matthew J. Schellenberg,
Stuart K. Calderwood
Affiliations
Heeyoun Bunch
Department of Applied Biosciences, College of Agriculture and Life Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Jaehyeon Jeong
Department of Applied Biosciences, College of Agriculture and Life Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Keunsoo Kang
Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan 31116, Republic of Korea
Doo Sin Jo
School of Life Sciences, BK21 Four KNU Creative Bioresearch Group, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Anh T. Q. Cong
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
Deukyeong Kim
School of Applied Biosciences, College of Agriculture and Life Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Donguk Kim
School of Applied Biosciences, College of Agriculture and Life Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Dong-Hyung Cho
School of Life Sciences, BK21 Four KNU Creative Bioresearch Group, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
You Mie Lee
Vessel-Organ Interaction Research Center, VOICE (MRC), Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
Benjamin P. C. Chen
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Matthew J. Schellenberg
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
Stuart K. Calderwood
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
RNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signalling in humans. Here, we report a novel function of the breast cancer 1 (BRCA1)-BRCA1-associated ring domain 1 (BARD1) complex in this process. We found that BRCA1 is phosphorylated at S1524 by the kinases ataxia-telangiectasia mutated and ATR during gene activation, and that this event is important for productive transcription. Our biochemical and genomic analyses showed that the BRCA1-BARD1 complex interacts with TOP2B in the EGR1 transcription start site and in a large number of protein-coding genes. Intriguingly, the BRCA1-BARD1 complex ubiquitinates TOP2B, which stabilizes TOP2B binding to DNA while BRCA1 phosphorylation at S1524 controls the TOP2B ubiquitination by the complex. Together, these findings suggest the novel function of the BRCA1-BARD1 complex in the regulation of TOP2B and Pol II-mediated gene expression.
