Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

BRD4 (O60885) - Overview - Molecular Target Synopsis

Protein


BRD4, Bromodomain-containing protein 4
UniProt O60885

Also Known as BRD4_HUMAN, BRD4, HUNK1

Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure (PubMed:23589332, PubMed:23317504, PubMed:22334664). During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II (PubMed:23589332, PubMed:19596240, PubMed:16109377, PubMed:16109376, PubMed:24360279). Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II (PubMed:23086925). According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo (PubMed:22509028). In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B (PubMed:19103749). Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters (PubMed:23317504)., Isoform B: Acts as a chromatin insulator in the DNA damage response pathway. Inhibits DNA damage response signaling by recruiting the condensin-2 complex to acetylated histones, leading to chromatin structure remodeling, insulating the region from DNA damage response by limiting spreading of histone H2AFX/H2A.x phosphorylation. Binds acetylated histone H4 (PubMed:29176719). Interacts with p53/TP53; the interaction is direct (PubMed:23317504). Interacts (via CTD region) with CDK9 and CCNT1, acting as an associated component of P-TEFb complex (PubMed:16109376, PubMed:16109377, PubMed:23317504, PubMed:24360279). Interacts with RELA (when acetylated at 'Lys-310')(PubMed:19103749). Interacts (via NET domain) with NSD3, CHD4, BICRA and ATAD5 (PubMed:21555454,PubMed:29176719). The interaction with BICRA bridges BRD4 to the GBAF complex (PubMed:29374058, PubMed:16109376, PubMed:16109377, PubMed:19103749, PubMed:21555454, PubMed:23317504). Interacts (via NET domain) with JMJD6 (via JmjC and N-terminal domains); the interaction is stronger in presence of ssRNA and recruits JMJD6 on distal enhancers (PubMed:24360279, PubMed:21555454, PubMed:29176719). Interacts with NSD3 (PubMed:29176719). Isoform B: interacts with NCAPD3 and SMC2 (PubMed:23728299).

6MAU
CRYSTAL STRUCTURE OF HUMAN BRD4(1) IN COMPLEX WITH CN210 (COMPOUND 19)
RCSB/PDB
Inspect Structure
See all 3D Structures for BRD4

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: BRD4 is active in the following subcellular-locations: chromosome, nucleus.
GO terms: BRD4 is active in the following subcellular-locations: chromosome, condensed nuclear chromosome, cytosol, nucleoplasm, nucleus.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project BRD4 has gain in 1 cell-lines, loss in 1 cell-lines and no signal in 1003 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: HS578T, SK_MEL_5, K_562

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: HCC1143, SNU-398, KYSE-70

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, IMR-90, K562

(see details)

RNA Interference


BRD4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: OVTOKO, BT20. (see details)

3D Structures


For BRD4 there are:
306 structures (370 chains) solved
264 are solved in complex with at least one small molecule ligand
3 are solved with an approved drug

BRD4 is solved in complex with the approved drug(s):

08J/MIDAZOLAM (3U5K_A, 3U5K_B, 3U5K_C, 3U5K_D),
LOC/COLCHICINE (4LZR_A),
08H/ALPRAZOLAM (3U5J_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


BRD4 has been screened with 1137 compounds (1735 bioactivities), 309 compounds have bioactivities that show binding affinity of <= 500nM (448 bioactivities). (see details)