Transcription

Our genetic blueprint is encoded in our DNA. In order for cells to function properly, our genetic information must be transcribed into a usable message, called RNA. We are interested in understanding  how transcription is regulated in normal cells and in diseased states.

RNA polymerases (RNAPs) are the cellular machinery responsible for transcribing genomic DNA into functional messages. Although polymerases have been extensively studied in bacteria and yeast, mammalian RNAPs have not been fully characterized. Using single particle cryo-Electron Microscopy, we have generated the first 3D reconstruction of human RNAP II bound to native DNA.  This approach is now being used to examine the structure of RNAP II isolated from human cancer cells while interacting with the tumor suppressor protein, BRCA1. We call this important new area of research “Structural Oncology”. Mutations in BRCA1, the breast cancer susceptibility protein, are heavily implicated in familial breast and ovarian cancers that are classified as “triple negative”. Triple negative tumors lack estrogen receptors, progesterone receptors and Her2 expression that are commonly used drug targets to enhance treatment options for other forms of breast cancer. Thus, patients afflicted with triple negative cancers have limited treatment options and succumb to recurrence in less time following conventional therapy. Under normal conditions, the BRCA1 protein acts as a tumor suppressor, helping correct breaks in genomic DNA and ensure fidelity in newly synthesized mRNA. Defects in these regulatory processes lead to genomic instability and to tumor initiation. Understanding the molecular basis for triple negative breast cancer induction related to BRCA1 mutations could significantly contribute to the development of new treatment options for patients afflicted with this aggressive disease.