Dr. Arnold Berk’s laboratory studies the molecular interactions that regulate transcription in mammalian cells, focusing particular attention on transcription factors encoded by oncogenes and tumor suppressors and the regulation of cell replication. Since the decision to initiate transcription is the key control point regulating expression of most genes, transcriptional regulation determines the properties of both normal and abnormal cells.
Many of the lab’s projects involve proteins expressed early during infection by DNA viruses because these proteins have evolved to interact with key host cell regulatory proteins in order to maximize the yield of progeny virions. Consequently, they have directed Berk’s lab to critical cellular regulatory proteins with which they interact, such as p53, the Retinoblastoma protein family, the mediator of transcription complex and chromatin modifying complexes. In recent years, the lab discovered that the adenovirus large E1A protein activates transcription from viral promoters by making a high affinity interaction with a specific subunit of the mediator of transcription complex, MED23. The lab also found that activator-mediator interactions stimulate pre-initiation complex assembly on promoter DNA, and that these interactions also stimulate a post-recruitment step in transcription initiation responsible for the "paused polymerases" recently observed at most mammalian promoters.
Berk and his lab also study inactivation of the p53 tumor suppressor by adenovirus E1B. Recently, they discovered that repression involves sequestration of p53 in subnuclear domains called PML-nuclear bodies. This results from transient covalent attachment of SUMO1 proteins to monomers in a large molecular lattice of E1B and p53. The recent work can explain the fascinating enigma of how all p53 molecules are inactivated when only ~1 percent are modified by SUMO1. Recently, the lab applied "ChIP on chip" methodology to discover how the adenovirus small e1a protein forces contact-inhibited human cells to proliferate: small e1a directly re-localizes major chromatin-modifying complexes on a global genomic scale. Finally, the lab also works in the area of gene therapy and has engineered an adenovirus-Epstein-Barr virus hybrid vector that introduces stable episomes into infected cells in tissues of intact animals.
Selected Cancer-Related Publications:
Pennella MA, Liu Y, Woo JL, Kim CA, Berk AJ. Adenovirus E1B 55-kilodalton protein is a p53-SUMO1 E3 ligase that represses p53 and stimulates its nuclear export through interactions with promyelocytic leukemia nuclear bodies. J Virol. 2010 Dec;84(23):12210-25. Epub 2010 Sep 22.
Ferrari R, Berk AJ, Kurdistani SK. Viral manipulation of the host epigenome for oncogenic transformation. Nat Rev Genet. 2009 May;10(5):290-4.
Balamotis MA, Pennella MA, Stevens JL, Wasylyk B, Belmont AS, Berk AJ. Complexity in transcription control at the activation domain-mediator interface. Sci Signal. 2009 May 5;2(69):ra20.
Horwitz GA, Zhang K, McBrian MA, Grunstein M, Kurdistani SK, Berk AJ. Adenovirus small e1a alters global patterns of histone modification. Science. 2008 Aug 22;321(5892):1084-5.
Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK. Epigenetic reprogramming by adenovirus e1a. Science. 2008 Aug 22;321(5892):1086-8.