TY - JOUR
T1 - Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly
AU - Denko, Nicholas
AU - Wernke-Dollries, Kara
AU - Johnson, Amber Buescher
AU - Hammond, Ester
AU - Chiang, Cheng Ming
AU - Barton, Michelle Craig
PY - 2003/2/21
Y1 - 2003/2/21
N2 - Hypoxia is a growth inhibitory stress associated with multiple disease states. We find that hypoxic stress actively regulates transcription not only by activation of specific genes but also by selective repression. We reconstituted this bimodal response to hypoxia in vitro and determined a mechanism for hypoxia-mediated repression of transcription. Hypoxic cell extracts are competent for transcript elongation, but cannot assemble a functional preinitiation complex (PIC) at a subset of promoters. PIC assembly and RNA polymerase II C-terminal domain (CTD) phosphorylation were blocked by hypoxic induction and core promoter binding of negative cofactor 2 protein (NC2α/β, Dr1/DrAP1). Immunodepletion of NC2β/Dr1 protein complexes rescued hypoxic-repressed transcription without alteration of normoxic transcription. Physiological regulation of NC2 activity may represent an active means of conserving energy in response to hypoxic stress.
AB - Hypoxia is a growth inhibitory stress associated with multiple disease states. We find that hypoxic stress actively regulates transcription not only by activation of specific genes but also by selective repression. We reconstituted this bimodal response to hypoxia in vitro and determined a mechanism for hypoxia-mediated repression of transcription. Hypoxic cell extracts are competent for transcript elongation, but cannot assemble a functional preinitiation complex (PIC) at a subset of promoters. PIC assembly and RNA polymerase II C-terminal domain (CTD) phosphorylation were blocked by hypoxic induction and core promoter binding of negative cofactor 2 protein (NC2α/β, Dr1/DrAP1). Immunodepletion of NC2β/Dr1 protein complexes rescued hypoxic-repressed transcription without alteration of normoxic transcription. Physiological regulation of NC2 activity may represent an active means of conserving energy in response to hypoxic stress.
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U2 - 10.1074/jbc.M212534200
DO - 10.1074/jbc.M212534200
M3 - Article
C2 - 12477712
AN - SCOPUS:0037458545
SN - 0021-9258
VL - 278
SP - 5744
EP - 5749
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -