Research Area: Genome Instability and Ageing
The accurate replication and transmission of genetic material is of fundamental importance for cellular homeostasis and organism viability. Yet, cells are continually exposed to environmental and endogenous genotoxic agents that threaten DNA integrity. To protect their genomic stability, cells mount a complex network of DNA damage response pathways that activate cell cycle checkpoints, coordinate DNA repair, regulate gene expression and, if necessary, induce cell death. DNA damage signalling and repair is a powerful barrier to tumourigenesis, and defects in these pathways promote cell proliferation and genomic instability in premalignant lesions. Critically, genomic instability is also a hallmark of ageing. As such, the accumulation of DNA damage promotes not only the normal ageing process but is also linked to pre-mature aging syndromes and to the onset of age-associated neurodegenerative diseases.
Our lab seeks to understand how cells detect, signal and repair DNA damage to protect genomic stability. We are particularly interested in identifying and characterizing new regulators of the DNA damage response. We generally pursue the following questions:
Somatic cells have finite replicative lifespans because telomeres undergo progressive shortening after DNA replication, which can lead to genome instability and induce cellular senescence. To counteract telomere erosion and to achieve replicative immortality, cells activate one of two distinct telomere maintenance mechanisms (TMMs). The first mechanism relies on the re-expression of the reverse transcriptase telomerase. The second mechanism, known as alternative lengthening of telomeres (ALT), extends telomeres by upregulating homology-directed DNA recombination pathways. ALT is employed by 10-15% of tumours and is often associated with aggressive clinicopathologic behavior, which is likely due to the fact that these tumours are genomically highly unstable and are resistant to therapies based on telomerase inhibition. The molecular mechanisms underpinning ALT are very poorly understood. We have recently identified the protein SLX4IP as a novel regulator of telomere recombination specifically in ALT-positive cancer cells. While SLX4IP is dispensable for telomere maintenance in telomerase-positive cells, its loss in ALT cancer cells leads to telomere hyper-recombination and genome instability. The clinical importance of SLX4IP is highlighted by its frequent inactivation in ALT-positive osteosarcomas.
We offer a PhD project that will investigate how ALT pathways interact with homeostatic pathways and microenvironmental cues to ensure telomere length maintenance. Specifically, we aim to:
Investigate how the cell microenvironment influences telomere maintenance and vice versa.
The tumour microenvironment (TME) plays a significant role in cancer progression and metastasis. Indeed, TME changes such as hypoxic stress lead to the dysregulation of DNA repair pathways, which then contributes to the genomic instability that is a hallmark of cancer. Whether changes in the cellular microenvironment influence telomere length homeostasis has so far not been addressed. We will employ 3D spheroid tumour models to uncover and dissect interactions between the TME and ALT- and telomere-mediated telomere length homeostasis.
We are an interdisciplinary lab that employs a wide range of molecular, genetic, cell biological and systems biology approaches. Applied methods include:
We work primarily with mammalian 2D and 3D tissue cultures.
We seek an ambitious and pro-active student to join our new research team. Experience in mammalian tissue culture and omics approaches are desirable but not required. The student will receive extensive training in all relevant techniques.