Biochemical Studies of Eukaryotic Messenger RNA Synthesis (AMGEN Award lecture)

Our laboratory has exploited a straightforward biochemical approach to identier and characterize components of the RNA polymerase II transcriptional machinery. Recently, these studies led to tile discovery of two novel cellular proteins, Elongin A and ELL, which stimulate elongation by RNA polymerase II by suppressing transient pausing by polymerase at many sites along the DNA. Elongin A contains an inducible elongation activation domain that is potently activated by the Elongin BC coinplex. The Elongin BC complex is a cellular target of the von ttippel-Lindau tumor suppressor gene product, which is capable of negatively regulating Elongin A transcriptional activity in vitro by binding the Elongin BC complex and preventing it front activating Elongin A. The human ELL gene on chromosome 19p13.1 undergoes frequent translocations with the trithoraxdike M LL gene on chromosome [ 1q23 in acute myeloid leukemia. The ELL protein contains two unusual overlapping functional domains that govern its interaction wieh RNA polymerase II and the ternary elongation colnplex. The MLL-I:;LL eranslocation results in disruption of one of these ELL functional domains.