Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration.
Retroviral integrase (IN) proteins catalyze the permanent integration of proviral genomes into host DNA with the help of cellular cofactors. Lens epithelium-derived growth factor (LEDGF) is a cofactor for lentiviruses, including human immunodeficiency virus type 1 (HIV-1), and targets lentiviral integration toward active transcription units in the host genome. In contrast to lentiviruses, murine leukemia virus (MLV), a gammaretrovirus, tends to integrate near transcription start sites. Here, we show that the bromodomain and extraterminal domain (BET) proteins BRD2, BRD3, and BRD4 interact with gammaretroviral INs and stimulate the catalytic activity of MLV IN in vitro. We mapped the interaction site to a characteristic structural feature within the BET protein extraterminal (ET) domain and to three amino acids in MLV IN. The ET domains of different BET proteins stimulate MLV integration in vitro and, in the case of BRD2, also in vivo. Furthermore, two small-molecule BET inhibitors, JQ1 and I-BET, decrease MLV integration and shift it away from transcription start sites. Our data suggest that BET proteins might act as chromatin-bound acceptors for the MLV preintegration complex. These results could pave a way to redirecting MLV DNA integration as a basis for creating safer retroviral vectors.
Institute of Virology, Hannover Medical School, Hannover, Germany.
Saumya Shree
SS
Gupta
Tobias
T
Maetzig
Goedele N
GN
Maertens
Azar
A
Sharif
Michael
M
Rothe
Magdalena
M
Weidner-Glunde
Melanie
M
Galla
Axel
A
Schambach
Peter
P
Cherepanov
Thomas F
TF
Schulz
D020816:Amino Acid Motifs; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D009052:Leukemia Virus, Murine / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012192:Retroviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D002843:Chromatin; D019426:Integrases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014764:Viral Proteins; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human