6kn5
From Proteopedia
Crystal structure of AFF4 C-terminal domain
Structural highlights
Disease[AFF4_HUMAN] Note=A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a MLL-AFF4 fusion protein. Function[AFF4_HUMAN] Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.[1] [2] [3] Publication Abstract from PubMedAs approximately 70% of human breast tumors are estrogen receptor alpha (ERalpha)-positive, estrogen and ERalpha play essential roles in breast cancer development. By interrupting the ERalpha signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERalpha) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERalpha signaling pathway at chromatin level. Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha.,Gao Y, Chen L, Han Y, Wu F, Yang WS, Zhang Z, Huo T, Zhu Y, Yu C, Kim H, Lee M, Tang Z, Phillips K, He B, Jung SY, Song Y, Zhu B, Xu RM, Feng Q Commun Biol. 2020 Apr 7;3(1):165. doi: 10.1038/s42003-020-0898-0. PMID:32265480[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Chen, L J | Xu, R M | Yang, W S | Aff4 | Histone acetylation | Transcription
