Untangling chromatin to find novel anti-cancer targets
Our lab is a part of the oldest cancer research center, Roswell Park Cancer Institute, which was founded by surgeon Dr. Roswell Park in in 1898. The lab was started in 2008 within the Department of Cell Stress Biology, and according to Google, is the only department with this name. The major goal of our research is the identification of a way to gain control over cancer, i.e. finding novel targets for anti-cancer treatment and approaches to modulate these targets. Several novel small molecules with anti-cancer properties were identified in our lab. One of them, curaxin CBL0137, is currently being tested in clinical trials.
Curaxins were discovered in a cell-based screening for novel type of activators of tumor suppressor p53. The search for the mechanism of action of curaxins brought us to the field of chromatin biology, since curaxins appeared to be the “first in the class” – pure “chromatin damaging” compounds. The current focus of our research is understanding the chromatin alterations in cancer, the reasons chromatin destabilization is more toxic for tumor than for normal cells, how chromatin stability is regulated, and whether it is possible to utilize some chromatin remodeling factors, e.g. histone chaperone, as targets for anti-cancer treatment.
Laura's Thesis paper is finally published in Oncogene!
Histone chaperone FACT is essential to overcome replication stress in mammalian cells
Laura Prendergast , Erin Hong , Alfiya Safina , Dante Poe , Katerina Gurova
Laura showed that during replication stress, when DNA polymerase is stalled, while MCM helicase move forward, creating ssDNA stretch which serves as a trigger of replication stress response, FACT is needed to keep MCM bound to chromatin. In the absence of FACT MCM detaches from chromatin and signal to replication stress response is vanished. Without proper coordination of events orchestrated by replication stress response mechanism, cells accumulate DNA damage and die.
June 2020. Poorva's 2nd Thesis paper is published in iScience!
Prevention of Chromatin Destabilization by FACT Is Crucial for Malignant Transformation
Poorva Sandlesh , Alfiya Safina , Imon Goswami , Laura Prendergast , Spenser Rosario , Eduardo C Gomez , Jianmin Wang , Katerina V Gurova
Poorva with the help of other lab members showed that transformed malignant cells need FACT not for facilitating of their high rates of transcription but for preventing destabilization of chromatin, caused by intensive transcription. So there are more and more data showing that FACT may be major sensor and keeper of chromatin stability in mammalian cells. Next step is to test if it performs the same function in normal cells with high rates of transcription in vivo (i.e. in animals, not in petri dish:)
October 2019: First ever Histone Chaperone workshop successful happened! Fondele Resort, Crete, Greece