MPI for Biology of 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. Stephanie Panier’s team is investigating the molecular mechanisms underlying the cellular response to DNA damage and how the dysfunction of these response pathways contributes to genome instability-triggered and ageing-associated diseases.
Our research: 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 apoptosis. DNA damage signaling 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.
The overarching question of the group’s research program is how cells detect and repair DNA damage to safeguard their genetic information. The Panier lab is particularly interested in understanding the regulatory mechanisms underpinning the recombination-dependent repair of DNA lesions.
One key function of the recombination machinery is to deal with the consequences of unresolved DNA replication stress. DNA replication forks are constantly challenged by DNA lesions and other impediments such as transcribing RNA polymerases or unusual DNA structures. If not resolved in a timely manner, these obstacles can cause replication forks to stall and collapse and as such represent a major source of genomic instability. The homologous recombination (HR) machinery is critical for the protection of stalled forks and also helps to restore the integrity of collapsed forks. The Panier lab investigates the regulatory mechanisms that surround this machinery at stressed replication forks.
The group’s interests in DNA recombination also extend to telomeres, which are the DNA-protein structures that cap the ends of linear eukaryotic chromosomes. Telomeres are critical for genome stability as they protect chromosome ends from degradation and fusion by cellular DNA repair processes. In non-malignant somatic cells, telomeres undergo progressive shortening after DNA replication, which eventually results in replicative senescence and checkpoint-driven cell death, a phenomenon, which plays a key role in the ageing of the organism. In contrast, tumour cells are able to counteract telomere attrition, and thus achieve replicative immortality, by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. ALT-positive tumours account for approximately 10-15% of all tumours and are mostly associated with a poor prognosis because of their complex karyotypes and lack of targeted therapies. The Panier lab investigates the molecular mechanisms underpinning this telomere maintenance pathway. They are especially interested in identifying the factors and cues that drive ALT establishment and maintenance and in dissecting the regulatory pathways that fine-tune telomere recombination reactions.
Our goals: The group’s goal is to identify and characterize factors that are involved in the recombination-dependent repair of DNA lesions, particularly in the context of stressed replication forks and telomeres. They work towards identifying molecular weaknesses that can be exploited to develop new treatment approaches for genome instability-triggered and ageing-associated diseases.
Our methods/techniques: The Panier group is an interdisciplinary lab that employs a wide range of molecular, genetic, cell biological and systems biology approaches, including state-of-the-art microscopy and CRISPR-Cas-based genetics and screening. They work primarily with mammalian cells.