TY - JOUR
T1 - Transcription elongation regulator 1 (TCERG1) regulates competent RNA polymerase II-mediated elongation of HIV-1 transcription and facilitates efficient viral replication
AU - Coiras, Mayte
AU - Montes, Marta
AU - Montanuy, Immaculada
AU - López-Huertas, María R.
AU - Mateos, Elena
AU - Le Sommer, Caroline
AU - Garcia-Blanco, Mariano A.
AU - Hernández-Munain, Cristina
AU - Alcamí, José
AU - Suñé, Carlos
N1 - Funding Information:
This work was supported by grants from the Spanish Ministry of Science and Innovation (BFU2011-24577), the Foundation for Research and Prevention of AIDS in Spain (FIPSE-36768/08), and the Andalusian Government (Excellence Project CVI-4626/2009) to C.S.; by the Spanish Ministry of Science and Innovation (BFU2009-08796), and the Andalusian Government (Excellence Project CTS-6587) to C.H.M; and by FIPSE (360924/10), the Spanish Ministry of Economy and Competitiveness (SAF2010-18388; FIS PI0120506), the Spanish Ministry of Health (EC11-285, -278), Instituto de Salud Carlos III, AIDS Network ISCIII-RETIC (RD12/0017/0015), and the Health Programme 2009 on Combined Highly Active Anti-Retroviral Microbicides (CHAARM) to M.C. and J.A. Support from the European Region Development Fund, ERDF (FEDER) is also acknowledged. M.M. was supported by a fellowship from the Spanish Ministry of Education (FPU program). M.R.L.H was supported by a fellowship from the European Union (CHAARM). C.L.S. was funded by a fellowship from the Foundation for Medical Research (F.R.M., France) and by funds from NIH RO1 GM071037 (USA) to M.A.G-B. We are grateful to members of the laboratories for their helpful suggestions, critical discussions, and comments. We also appreciate the secretarial assistance of Mrs Olga Palao. We thank Centro de Transfusiones from Autonomous Community of Madrid, Spain, for providing the buffy coats.
PY - 2013/10/28
Y1 - 2013/10/28
N2 - Background: Control of RNA polymerase II (RNAPII) release from pausing has been proposed as a checkpoint mechanism to ensure optimal RNAPII activity, especially in large, highly regulated genes. HIV-1 gene expression is highly regulated at the level of elongation, which includes transcriptional pausing that is mediated by both viral and cellular factors. Here, we present evidence for a specific role of the elongation-related factor TCERG1 in regulating the extent of HIV-1 elongation and viral replication in vivo. Results: We show that TCERG1 depletion diminishes the basal and viral Tat-activated transcription from the HIV-1 LTR. In support of a role for an elongation mechanism in the transcriptional control of HIV-1, we found that TCERG1 modifies the levels of pre-mRNAs generated at distal regions of HIV-1. Most importantly, TCERG1 directly affects the elongation rate of RNAPII transcription in vivo. Furthermore, our data demonstrate that TCERG1 regulates HIV-1 transcription by increasing the rate of RNAPII elongation through the phosphorylation of serine 2 within the carboxyl-terminal domain (CTD) of RNAPII and suggest a mechanism for the involvement of TCERG1 in relieving pausing. Finally, we show that TCERG1 is required for HIV-1 replication. Conclusions: Our study reveals that TCERG1 regulates HIV-1 transcriptional elongation by increasing the elongation rate of RNAPII and phosphorylation of Ser 2 within the CTD. Based on our data, we propose a general mechanism for TCERG1 acting on genes that are regulated at the level of elongation by increasing the rate of RNAPII transcription through the phosphorylation of Ser2. In the case of HIV-1, our evidence provides the basis for further investigation of TCERG1 as a potential therapeutic target for the inhibition of HIV-1 replication.
AB - Background: Control of RNA polymerase II (RNAPII) release from pausing has been proposed as a checkpoint mechanism to ensure optimal RNAPII activity, especially in large, highly regulated genes. HIV-1 gene expression is highly regulated at the level of elongation, which includes transcriptional pausing that is mediated by both viral and cellular factors. Here, we present evidence for a specific role of the elongation-related factor TCERG1 in regulating the extent of HIV-1 elongation and viral replication in vivo. Results: We show that TCERG1 depletion diminishes the basal and viral Tat-activated transcription from the HIV-1 LTR. In support of a role for an elongation mechanism in the transcriptional control of HIV-1, we found that TCERG1 modifies the levels of pre-mRNAs generated at distal regions of HIV-1. Most importantly, TCERG1 directly affects the elongation rate of RNAPII transcription in vivo. Furthermore, our data demonstrate that TCERG1 regulates HIV-1 transcription by increasing the rate of RNAPII elongation through the phosphorylation of serine 2 within the carboxyl-terminal domain (CTD) of RNAPII and suggest a mechanism for the involvement of TCERG1 in relieving pausing. Finally, we show that TCERG1 is required for HIV-1 replication. Conclusions: Our study reveals that TCERG1 regulates HIV-1 transcriptional elongation by increasing the elongation rate of RNAPII and phosphorylation of Ser 2 within the CTD. Based on our data, we propose a general mechanism for TCERG1 acting on genes that are regulated at the level of elongation by increasing the rate of RNAPII transcription through the phosphorylation of Ser2. In the case of HIV-1, our evidence provides the basis for further investigation of TCERG1 as a potential therapeutic target for the inhibition of HIV-1 replication.
KW - Pausing
KW - RNA polymerase II
KW - TCERG1
KW - Transcription elongation
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U2 - 10.1186/1742-4690-10-124
DO - 10.1186/1742-4690-10-124
M3 - Article
C2 - 24165037
AN - SCOPUS:84886226760
SN - 1742-4690
VL - 10
JO - Retrovirology
JF - Retrovirology
IS - 1
M1 - 124
ER -