The Genome Integrity Unit investigates how cells maintain their DNA health with specific interests in cancer and early development.
Our genome is an instruction manual that guides biological activity. When our genetic code is disrupted this can have serious health consequences. To maintain healthy DNA our cells have evolved specific mechanisms to protect the genome. This includes arranging the DNA into proper chromosomal structures, ensuring the DNA is accurately replicated each time the cell divides, scanning DNA for damage, and when necessary promoting DNA repair. If these functions are compromised the genome can become damaged. Cells with unstable genomes often choose to die to prevent potential negative consequences. However, if cells with unhealthy DNA continue to proliferate, this may promote cancer. Because cancers often display damaged or unstable genomes, this presents a therapeutic opportunity to specifically target and kill tumour cells.
We are specifically interested in understanding:
Associate Professor Anthony (Tony) Cesare is Head of the Genome Integrity Unit at CMRI.
We identified that telomere-loops (t-loops) function specifically to regulate ATM activity at human and mouse telomeres and collaborated with the Boulton Lab from the Crick Institute to identify how t-loops are resolved during S-phase to enable telomere replication. We are currently working to decipher the cell-cycle dependent telomere proteome and determine how t-loops are resolved in mitosis during non-canonical telomere deprotection.
We identified that nuclear actin polymerization alters nuclear architecture and promotes replication stress repair and characterized the regulatory pathway. Research in our lab continues to study how nuclear and chromatin architecture is regulated during DNA replication to promote genome stability. Additionally, we collaborate with Patrick Tam and the CMRI Embryology Unit to study the unique properties of replication in rapidly dividing embryonic stem cells.
Our studies of telomere biology and DNA replication led us unexpectedly to identify how lethal replication stress induces cell death specifically during mitosis through a pathway of cohesion fatigue and non-canonical telomere deprotection. We have expanded this study through collaboration with the Sydney West Radiation Oncology Network to focus on mechanisms of cell death in response to chemotherapeutic and radiation-oncology intervention.
Pragathi Masamsetti – Post-doctoral scientist CMRI Embryology Unit with Patrick Tam
Ronnie Low – Ph.D. Student University of Melbourne/WEHI with Tracy Putoczki
Patrick Stalder – Ph.D. Student ETH Zürich Institute of Molecular Systems Biology with Paola Picotti
Jessie Zhang – Medical Doctor, Concord Repatriation General Hospital
Ka Sin (Cassie) Mak - Regulatory Affairs Associate, MSD Pharmaceuticals
Sonja Frolich – Post-doctoral scientist University of Adelaide Research Centre for Infection Diseases, Danny Wilson Laboratory
Tara Bartolec – Ph.D. student UNSW with Marc Wilkins
Garima Moudgil – Medical Student, University of Queensland
Meet Georgia Kafer, Genome Integrity
The Genome Integrity Unit has published in Nature and other top journals.