A Bromodomain Protein, MCAP, Associates with Mitotic Chromosomes and Affects G₂-to-M Transition

Abstract

We describe a novel nuclear factor called mitotic chromosome-associated protein (MCAP), which belongs to the poorly understood BET subgroup of the bromodomain superfamily. Expression of the 200-kDa MCAP was linked to cell division, as it was induced by growth stimulation and repressed by growth inhibition. The most notable feature of MCAP was its association with chromosomes during mitosis, observed at a time when the majority of nuclear regulatory factors were released into the cytoplasm, coinciding with global cessation of transcription. Indicative of its predominant interaction with euchromatin, MCAP localized on mitotic chromosomes with exquisite specificity: (i) MCAP-chromosome association became evident subsequent to the initiation of histone H3 phosphorylation and early chromosomal condensation; and (ii) MCAP was absent from centromeres, the sites of heterochromatin. Supporting a role for MCAP in G 2 /M transition, microinjection of anti-MCAP antibody into HeLa cell nuclei completely inhibited the entry into mitosis, without abrogating the ongoing DNA replication. These results suggest that MCAP plays a role in a process governing chromosomal dynamics during mitosis.

Brd4 links chromatin targeting to HPV transcriptional silencing

“…The recent reports that Brd4 can function as a transcriptional coactivator capable of stimulating the kinase and elongation activities of PTEFb Yang et al 2005) provides the first evidence for Brd4's involvement in transcription, in addition to its previously characterized roles in cell proliferation (Dey et al 2000;Houzelstein et al 2002), DNA replication (Maruyama et al 2002), and gene rearrangement found in t(15;19)-associated carcinomas (French et al 2003). Our finding that Brd4 can also act as a transcriptional corepressor implicated in HPV gene silencing not only extends the functional properties of Brd4 but also exemplifies a dual role of a typical transcription cofactor in gene activation and repression (Thomas and Chiang 2006).…”

“…The two tandem bromodomains found in TAF1 can bind simultaneously to two acetyl-lysine residues separated by seven or eight amino acids, such as acetylated K5/K12 and K8/ K16 of histone H4 (Jacobson et al 2000). Other proteins with two tandem bromodomains, followed by an additional extraterminal (ET) domain, constitute the BET subfamily, which includes yeast Bdf1 and Bdf2, Drosophila Fs(1)h, and mammalian Brd2/Ring3/Fsrg1, Brd3/ Orfx/Fsrg2, Brd4/MCAP, and Brd5/Brdt (Denis et al 2000;Dey et al 2000;Matangkasombut et al 2000;Houzelstein et al 2002;and references therein). A unique feature of the BET family members lies in their ability to bind mitotic chromosomes.…”

The bromodomain interaction module

“…There are four proteins in this subfamily, BRD2 [45], BRD3 [45], BRD4 [46] and BRDT [39]. Interestingly BET proteins are recruited to transcriptional start sites during mitosis [37,47,48] and the BET protein BRD4 has been shown to tether the positive transcription elongation factor (P-TEFb) to these sites via its unique C-terminus. As such, their interactions with histones have been studied in detail by several groups (Table 2).…”

Variations in the association of papillomavirus E2 proteins with mitotic chromosomes

“…The cellular bromodomain protein Brd4 is important for the association of the BPV1 E2 protein and viral genomes with mitotic chromosomes (7)(8)(9). Brd4 binds acetylated histones and is associated with chromatin throughout mitosis (10,11). Brd4 colocalizes with E2 in distinct speckles on mitotic chromosomes (7), and disruption of this interaction dissociates E2 from chromosomes (8).…”