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A multimeric complex of adenoviral small e1a and host cell proteins condenses chromatin


Classically, transcriptional regulation is discussed as the recruitment and assembly of RNA Polymerase II (Pol II) and its pre-initiation complex (PIC) on promoter regions of DNA. However, upstream of this event, transcriptional regulation also requires the regulation of chromatin structure between repressive, condensed forms of chromatin and active, decondensed chromatin to allow transcription of cellular genes. Chromatin structure is regulated via modifications on the histone tails by histone modifiers, such as the lysine acetyltransferase p300/CBP(P300). The actions of repressive and activating transcriptional regulators binding to chromatin result in the highly regulated expression of genes in cells.

Adenovirus infects the terminally differentiated cells of the human respiratory epithelium. In order to create a conducive environment for the viral life cycle, the first viral protein expressed, e1a interacts with RB and p300 proteins to reprogram the host cell's epigenetic landscape. This dissertation shows that in order to repress some host cell genes, small e1a rearranges host cell chromatin into higher order condensed chromatin. Furthermore, the condensation of chromatin by small e1a requires the RB and P300 interaction, the maintenance of RB in its repressive state and e1a interactions with host cell chromatin modifiers. This work also hopes to refine the e1a-P300 interaction in e1a-induced chromatin condensation, and through those studies illuminate understanding of P300 and its protein domains.

Overall, further studies are required, but this work furthers understanding of the precise impact of adenoviral small e1a interactions with host cell proteins. More broadly, these studies further knowledge not only in how adenovirus oncogenic transformations, but overall cellular functions, that when mis-regulated, lead to cancer.

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