Transcription by RNA polymerase II (pol II) is a complex multistep process that encompasses pre-initiation complex (PIC) assembly, initiation, elongation and termination. The eleven-nineteen lysine-rich leukemia protein (ELL) is a pol II elongation factor that was initially discovered as a chromosomal translocation partner of the histone methyltransferase mixed lineage leukemia protein (MLL) in acute leukemia patients. Although biochemical and morphological studies in yeast and Drosophila have demonstrated significant insights into the role of ELL in transcription, the mechanisms underlying ELL function in mammalian systems and how its translocation with MLL leads to the progression of leukemia remain unclear. By applying combinations of gene depletion, subcellular localization, immunopurification and genome location analyses this study revealed that ELL bridges dynamic interactions that define two distinct rate-limiting steps in transcription. The first is early targeting and stabilization of the PIC containing pol II and the histone acetyltransferase p300. The second is stabilization and recruitment of additional transcription elongation factors including the positive transcription elongation factor b (P-TEFb), the AF4/FMR2 family member 4 protein (AFF4) and the pol II associated factor 1 (PAF1) to facilitate processive elongation and mRNA maturation. Furthermore, this study investigated the effects of MLL-ELL fusion and the human T cell lymphotropic/leukemia virus type I (HTLV-1) Tax oncoproteins on the assembly of cellular transcription complexes containing ELL. The results indicated that ELL is a "shared" or common transcriptional target of both MLL-ELL fusion and HTLV-1 Tax proteins. Enforced expression of either MLL-ELL fusion or Tax oncoprotein led to differential targeting of PIC containing ELL and p300 or elongation complex comprised of ELL in association with P-TEFb and AFF4 that culminate with activation of specific genes that promote proliferation. These finding suggest that due to its critical role in bridging dynamic interactions within the RNA pol II transcription cycle, ELL may represent a common point of vulnerability in multiple disease processes that is useful as a potential interface to exploit through therapeutic interventions.
|Advisor:||Broome, Carolyn, Gardner, Kevin|
|Commitee:||Byrnes, W. Malcolm, George, Matthew, McBride, Alison, Walters, Eric|
|Department:||Biochemistry & Molecular Biology|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 72/09, Dissertation Abstracts International|
|Subjects:||Molecular biology, Biochemistry|
|Keywords:||Elongation factors, Leukemia, Oncoproteins, RNA polymerase II, Transcription factors|
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