Arnold Berk
Member, Gene Regulation GPB Home Area
Immunity, Microbes & Molecular Pathogenesis GPB Home Area
Cell & Developmental Biology GPB Home Area
JCCC Gene Regulation Program Area
Professor, Microbiology, Immunology & Molecular Genetics
UCLA Presidential Chair
Molecular Cell Biology
Professor June Lascelles Scholar
University of California, Los Angeles, USA
Title: Adenovirus E1A repression of cytokine response pathways by co-opting RB protein function
Biography
Biography: Arnold Berk
Abstract
To analyze control of host cell gene expression by adenovirus small E1A protein, we performed experiments with structure-based e1a mutants completely defective for binding to either p300/CBP or RB-family proteins. RNA-seq and ChIP-seq for e1a, RB1, RBL1 (p107), RBL2 (p130), p300, pol2, H3K9ac, H3K18ac, H3K27ac and H3K4me1 revealed that p300/CBP acetylation of RB1 K873/K874 (1) in a trimeric p300/CBP-e1a-RB complex (2) inhibits RB phosphorylation by cyclin/CDKs, thereby locking RB1 in a repressing conformation (1,3) that interacts with repressive chromatin modifying enzymes (3). e1a then delivers these repressing p300/CBP-e1a-RB complexes to host cell genes that have unusually high p300 association within the gene body and are highly enriched for cytokine signaling pathway genes, repressing their transcription. The p300/CBP-e1a-RB complex condenses chromatin as assayed by confocal microscopy of an amplified lacO array (4). e1a-induced chromatin condensation requires simultaneous binding of e1a to an RB and p300/CBP, e1a-binding to the chromatin remodeler p400 (5), HDAC activity, p300 KAT activity, the p300 bromo-ring-PHD domain (6), and acetylation of RB1 K873/K874 (2) and e1a K239 (7). Our data suggests a model for how the p300/CBP-e1a-RB complex spreads over repressed genes. 1. Chan HM doi:10.1038/ 35083062 2. Wang HG PMID 8416379 3. Dick FA, Rubin SM doi:10.1038/nrm3567 4. Verschure PJ doi: 10.1128 /MCB.25.11.4552-4564 5. Fuchs M doi:10.1016/S0092-8674(01) 00450-0 6. Delvecchio M doi:10.1038/nsmb.2642 7. Zhang Q doi: 10.1073/pnas.011283598