Uncovering chromatin aberrations and molecular mechanisms associated with Alternative Lengthening of Telomeres in cancers
Worldwide Cancer Research
Monash University
Cancer cells gain replicative immortality by activating one of two telomere maintenance pathways. The aberrant ALT (alternative lengthening of telomeres) pathway is found in 15% of cancers. Recent studies have identified chromatin factor ATRX and histone H3.3, which are frequently mutated in ALT cancers to be the key contributors to the ALT process. This breakthrough finding was facilitated by our original discoveries describing the roles of ATRX and H3.3 in controlling telomere function. Developing treatments for ALT cancers is challenging because of the current poor understanding of the molecular mechanisms underlying ALT activation and maintenance. This proposed study aims to uncover the molecular events and chromatin aberrations linked to ATRX/H3.3 mutations and ALT by pursuing the following aims. First, using the ALT cell models we have created, we will perform in-depth chromatin and genomics analyses to explore how a disrupted KDM4 network drives ALT and oncogenesis in ATRX/H3.3 mutant cancers. This follows from our recent discovery that mutant H3.3 protein inhibits the function of KDM4 histone demethylases and this leads to substantial genome-wide changes in chromatin and transcription profiles. Second, we will perform proteomics analyses to identify new protein factors and regulatory pathways driving and sustaining ALT. These studies will uncover new insights into the ALT pathway and identify new therapeutic targets for ALT cancers.
1.1 Normal biological development and functioning