Open AccessKaposi's Sarcoma-Associated Herpesvirus LANA-1 Interacts with the Short Variant of BRD4 and Releases Cells from a BRD4- and BRD2/RING3-Induced G 1 Cell CycleArrest
Author(s) -
Matthias Ottinger,
Thomas Christalla,
Kavita Nathan,
Melanie M. Brinkmann,
Abel ViejoBorbolla,
Thomas F. Schulz
Publication year - 2006
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.00804-06
Subject(s) - biology , brd4 , bromodomain , kaposi's sarcoma associated herpesvirus , chromatin , histone , cell cycle , nuclear protein , microbiology and biotechnology , cell , virology , genetics , transcription factor , virus , dna , gene , viral disease , herpesviridae
The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associatednuclear antigen 1 (LANA-1) is required for the replication of episomalviral genomes. Regions in its N-terminal and C-terminal domains mediatethe interaction with host cell chromatin. Several cellular nuclearproteins, e.g., BRD2/RING3, histones H2A and H2B, MeCP2, DEK, andHP1α, have been suggested to mediate this interaction. In thiswork, we identify the double-bromodomain proteins BRD4 and BRD3/ORFX asadditional LANA-1 interaction partners. The carboxy-terminal region ofthe short variant of BRD4 (BRD4S ) containing the highlyconserved extraterminal domain directly interacts with an element inthe LANA-1 carboxy-terminal domain. We show that ectopically expressedBRD4S and BRD2/RING3 delay progression into the S phase ofthe cell cycle in epithelial and B-cell lines and increase cyclin Epromoter activity. LANA-1 partly releases epithelial and B cells from aBRD4S - and BRD2/RING3-induced G1 cell cyclearrest and also promotes S-phase entry in the presence ofBRD4S and BRD2/RING3. This is accompanied by a reduction inBRD4S -mediated cyclin E promoter activity. Our data are inkeeping with the notion that the direct interaction of KSHV LANA-1 withBRD4 and other BRD proteins could play a role in the G1 /Sphase-promoting functions of KSHV LANA-1. Further, our data support amodel in which the LANA-1 C terminus contributes to a functionalattachment to acetylated histones H3 and H4 via BRD4 and BRD2, inaddition to the recently demonstrated direct interaction (A. J. Barbera, J. V. Chodaparambil, B. Kelley-Clarke, V. Joukov,J. C. Walter, K. Luger, and K. M. Kaye, Science311:856-861, 2006) of the LANA-1 N terminus with histones H2AandH2B.