The goal of our work is to identify genetic and protein networks that orchestrate telomere and genomic stability that may be targetable in cancer therapy. To achieve this we combine cellular imaging and proteomic platforms that provide a basis for further molecular dissection of the mechanisms involved in telomere dysfunction in human disease. Current projects in the lab include;
1. IDENTIFICATION OF FACTORS INVOLVED IN THE INDUCTION OF THE ALT PATHWAY
The Alternative Lengthening of Telomeres, ALT pathway is a mechanism of telomere length maintenance that is active in ~10% of human cancers. Many of these cancers affect the Central Nervous System and Pancreatic Neuroendocrine systems and unfortunately patients tend to have a poor prognosis. Since it was first identified in human cancers significant strides have been made in understanding the molecular biology of ALT. However, how the ALT pathway is activated has remained one of the most enigmatic aspects of telomere biology.
A confluence of recent evidence has suggested that ALT induction may be the result of an atypical chromatin structure at telomeres. We have recently discovered a system with which to rapidly induce ALT. This involves depletion of the histone chaperones, ASF1a and ASF1b. ASF1a and ASF1b coordinate the shuttling of histone proteins during DNA replication. This novel experimental system allows, for the first time, the direct identification of factors required for ALT activation.
We aim to utilize high throughput imaging platforms and genetic screens with this system to reveal the panoply of proteins involved in ALT induction and maintenance of the ALT pathway. This system may be suitable for use in small molecule screening to discover inhibitors of ALT in cancer. Testing and optimizing this is a high priority of our work.
2. INVESTIGATING CHROMATIN ASSEMBLY IN CANCER AND AGING.
Changes in the integrity of DNA can initiate a domino effect of the cellular changes that are the basis of cancer initiation and cellular atrophy that occurs with aging. Though intimately associated with DNA processes, certain non-genetic or "epigenetic" processes are also implicated in such processes. These invariably involve changes in the expression or activity of chromatin modifying enzymes.
Recent discoveries such as the identification of driver cancer mutations in histone genes and chromatin modifiers has put chromatin management and the assembly of chromatin during DNA replication and mitosis center stage in cancer research.