Brd4 Recruits P-TEFb to Chromosomes at Late Mitosis To Promote G₁ Gene Expression and Cell Cycle Progression

Abstract

Brd4, a bromodomain protein capable of interacting with acetylated histones, is implicated in transmitting epigenetic memory through mitosis. It also functions as an associated factor and positive regulator of P-TEFb, a Cdk9-cyclin T1 heterodimer that stimulates transcriptional elongation by phosphorylating RNA polymerase II. In the present study, experiments were performed to determine whether these two functions of Brd4 are interrelated and, if so, how they may impact cell cycle progression. Our data demonstrate that while the P-TEFb level remains constant, the Brd4-P-TEFb interaction increases dramatically in cells progressing from late mitosis to early G₁. Concurrently, P-TEFb is recruited to chromosomes, beginning around mid- to late anaphase and before nuclear envelope/lamina formation and nuclear import of other general transcription factors. Importantly, the recruitment of P-TEFb depends on Brd4. Abrogation of this process through Brd4 knockdown reduces the binding of P-TEFb to and expression of key G₁ and growth-associated genes, leading to G₁ cell cycle arrest and apoptosis. Because P-TEFb is synonymous with productive elongation, its recruitment by Brd4 to chromosomes at late mitosis may indicate those genes whose active transcription status must be preserved across cell division.

ACKNOWLEDGMENTS

We thank Wanichaya Ramey for technical assistance.

This work was supported by grants from the National Institutes of Health (AI41757) and The Susan G. Komen Breast Cancer Foundation (BCTR71506) to Q.Z.