TY - JOUR
T1 - The Functions of BET Proteins in Gene Transcription of Biology and Diseases
AU - Cheung, Ka Lung
AU - Kim, Claudia
AU - Zhou, Ming Ming
N1 - Funding Information:
This work was supported in part by the research grants from Crohn’s & Colitis Foundation (KLC; Award# 579304) and the National Institutes of Health (M-MZ; R01AI124465, R01CA239165, R01AG072562).
Publisher Copyright:
© Copyright © 2021 Cheung, Kim and Zhou.
PY - 2021/9/3
Y1 - 2021/9/3
N2 - The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins’ functions in mediating protein–protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.
AB - The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins’ functions in mediating protein–protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.
KW - bromodomain
KW - bromodomain and extra-terminal domain proteins
KW - cancer
KW - gene transcription
KW - inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85115192988&partnerID=8YFLogxK
U2 - 10.3389/fmolb.2021.728777
DO - 10.3389/fmolb.2021.728777
M3 - Review article
AN - SCOPUS:85115192988
VL - 8
JO - Frontiers in Molecular Biosciences
JF - Frontiers in Molecular Biosciences
SN - 2296-889X
M1 - 728777
ER -