| Summary: | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2002. === "February 2002." === Includes bibliographical references. === The E2F family of proteins plays a critical role in the regulation of genes that are essential for progression through the cell-cycle. Based upon sequence homology and functional properties, the E2F group can be subdivided into two subclasses (E2F1, 2, 3 versus E2F4 and 5). The work detailed in this study focuses on the cloning and characterization of a novel E2F family member, E2F6. E2F6 bears some sequence homology to the other E2Fs in the DP dimerization and DNA binding domains, but there is a high degree of divergence outside of those domains. Additionally, although the DP dimerization and DNA binding properties of E2F6 are similar to those of the other E2F family members, it is not regulated by the pocket proteim family and it is unable to activate transcription. Instead, it can act to repress the transcription of E2F responsive genes by countering the activity of the other E2F complexes. Therefore, E2F6 represents a new subclass of the E2F family. In an effort to more fully understand the mechanism behind the repressive abilities of E2F6, we screened for interacting proteins. RYBP, a member of the mammalian polycomb group, was identified by yeast-two-hybrid analysis as an E2F6-interacting protein. The RYBP-binding domain on E2F6 was highly conserved among all the E2F proteins, but the interaction was nevertheless specific to E2F6. In addition, E2F6 can associate with several other members of the polycomb transcriptional repression complex, including Ringla, Mel-18, mphl, and the oncogene Bmi1. Moreover, overexpression of E2F6 leads to a similar downregulation of p19ARF as exogenous Bmi1. These findings suggest that the biological properties of E2F6 could be mediated through its ability to recruit the polycomb complex. === (cont.) Finally, the presence of E2F6 in mammalian polycomb complexes sheds insight into how these complexes might bind to DNA. === by Jeffrey Michael Trimarchi. === Ph.D.
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