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Mechanistic insights into the roles of P-TEFb and its novel cofactors in tumorigenesis and HIV transcription

  • Author(s): He, Nanhai
  • Advisor(s): Zhou, Qiang
  • et al.
Abstract

Ongoing research in the field of transcription has given rise to the unappreciated role of elongation control as a rate limiting step for transcription, and the general transcription elongation factor P-TEFb therefore has taken the central stages. P-TEFb is composed of cyclin T1 and the cyclin-dependent kinase Cdk9. It stimulates transcription elongation by releasing the paused RNA Polymerase II (Pol II) through phosphorylating Pol II at Ser2 and antagonizing the effects of negative elongation factors. P-TEFb is not only essential for the transcription of the vast majority of cellular genes, but also critical for the expression of HIV genome. Elucidating how P-TEFb activity is controlled therefore plays a key role in advancing our understanding of cellular and disease-related transcription elongation.

The first part of this thesis presents my early Ph.D work, which focusing on the identification and characterization of a La-like protein PIP7S (also named as LARP7). I have shown that PIP7S binds and stabilizes nearly all the nuclear 7SK, which leading to sequestration and inactivation of P-TEFb. Consistent with the fact that PIP7S is frequently mutated in human tumors and the Drosophila homolog of PIP7S is a tumor suppressor, loss of PIP7S function disrupts epithelial differentiation and causes P-TEFb-dependent transformation.

The second part of this thesis introduces the identification of the Super Elongation Complex (SEC) and subsequent characterization of two of its subunits, AFF4 and ELL2. I have shown that through the bridging functions of AFF4 and Tat, P-TEFb and ELL2 combine to form a bifunctional elongation complex that greatly activates basal and HIV-1 transcription, respectively.

The third part of this thesis continues to dissect the functions of the other two SEC subunits ENL and AF9. I have shown that the homologous ENL and AF9 exist in separate SECs with similar but non-identical functions. ENL/AF9 also exists outside SEC when bound to Dot1L, which is found to inhibit SEC function. The YEATS domain of ENL/AF9 targets SEC to Pol II on chromatin through contacting the PAFc complex.

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