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Function and regulation of the Super Elongation Complexes in HIV-1 transcription

  • Author(s): Hsu, Joanne H.
  • Advisor(s): Zhou, Qiang
  • et al.
Abstract

In 2010, we discovered that the HIV-1 transactivator Tat interacts with a set of related transcription complexes containing two different classes of general transcription elongation factors, P-TEFb and ELL1/2, as well as the essential scaffolding protein AFF1/4. These complexes are called the Super Elongation Complexes (SECs). SECs are physically distinct from the two major P-TEFb complexes, the 7SK snRNP and the P-TEFb-Brd4 complex. In each SEC, AFF1/4 plays a scaffolding role in mediating the interaction between P-TEFb and ELL1/2. Our data show that the presence of Tat or AFF4 can significantly increase the half-life of ELL2, leading to significant elevation of levels of ELL2 and ELL2-P-TEFb-containing complex in cells. As a result of the increased amount of ELL2-P-TEFb-containing complex, both basal and Tat-dependent HIV-1 transcription is greatly enhanced in the presence of Tat or AFF4. In 2011, we found that ELL2 is targeted for polyubiquitination and degradation by the E3 ubiquitin ligase Siah1. Depletion of Siah1 promotes formation of SECs and SEC-dependent HIV transcription. The binding of AFF1/4 to ELL2 inhibits Siah1-mediated ELL2 polyubiquitination since Siah1 cannot access to and target ELL2 for polyuniquitination when ELL2 is being bound to AFF4. Together, our data illustrate that the control of ELL2 stability by Siah1 plays an important role in regulating SEC-dependent HIV-1 transcription and that Tat acts as a powerful activator of HIV-1 transcription by recruiting the stable, bifunctional elongation SEC complexes to the HIV-1 promoter. The link of the ubiquitination/proteolytic pathway to SECs will provide new opportunities for finding drugs and intervention strategies to modulate transcriptional elongation implicated in HIV/AIDS.

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