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11.04.2014

Team Targets Novel Pathway in Cancer

A team of scientists led by Ramin Shiekhattar, Ph.D., professor of biochemistry and molecular biology and human genetics, has identified an important mechanism that could be deregulated in cancer.

The article, “Integrator Regulates Transcriptional Initiation and Pause Release Following Activation,” composed by first author Alessandro Gardini, Ph.D., associate scientist at the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center, was published October 2 in Molecular Cell.

In human cells, the process known as transcription is regulated in multiple steps in which messenger RNAs (mRNA) are constructed from DNA to create proteins.

For the article, the researchers examined the transcriptional mechanisms of growth regulatory genes driven by epidermal growth factor, which is commonly exploited by cancer cells to sustain their development. The team highlighted the importance of RNA polymerase II pausing, a critical step that provides a barrier to transcriptional elongation, and the role of the multiprotein complex – Integrator.

“Integrator is only present in multicellular organisms, but the role of the Integrator complex in gene regulation has not been explored,” Gardini said. “Our study demonstrates the mechanism by which the Integrator complex assists RNA polymerase II to overcome barriers to elongation allowing the synthesis of long stretches of RNA.”

The research, conducted in mammalian cells and Drosophila, or fruit fly, showed the same results in both. According to these findings, the Integrator fulfills an evolutionary conserved role in regulating transcriptional elongation.

“Importantly, this study highlights the transition from initiation to elongation in cancer genes, regulated by the Integrator complex, as a critical step that could be targeted as a therapeutic strategy to stop proliferation of cancer cells,” said Shiekhattar, who also is Chief of the Division of Cancer Genomics and Epigenetics.

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