Dr. Pierre Billon

• Genome stability
• Genome editing

i. Investigating the mechanisms that promote CRISPR-based precision genome editing

DNA is the precious hereditary material of biological systems. Genomes contain genetic variants that can cause or predispose humans to disease. Emerging genome editing technologies have the potential to prevent or cure human disorders by eliminating pathogenic variants.

Genome editing technologies operate by triggering cellular DNA repair systems to resolve site-specific DNA lesions in living systems. The ability to introduce site-specific double-strand breaks by engineered nucleases or natural CRISPR-associated nucleases laid the foundations for the recent genome editing revolution. Modern sophisticated DSB-free genome editing agents, such as programmable base editors, prime-editors, and integrases, are exploited to generate precise base modifications, and insertions and deletions of desired sequences by inducing genomic lesions and by stabilizing certain repair intermediates at specific genomic sequences. These include single-strand breaks, deaminated bases, abasic sites, mismatched nucleotides, and flap structures. Accurate, specific, and predictable editing can be modulated by manipulating cellular DNA repair effectors. The lab aims to control DNA repair to improve the efficiency, accuracy, and safety of modern precision genome editing technologies.

The manipulation of the cellular DNA repair mechanisms will enable fine control of editing in therapeutic cellular systems. The insights gained from this work will not only improve the applications of genome editing technologies but also help generate important knowledge on the fundamental mechanisms of DNA repair. Adequate control of the cellular response to DNA damage will lay the foundation for precise therapeutic genome editing and contribute to precisely modeling and functionally studying pathogenic variants.

ii. Investigating DNA repair in cancer

Genomic instability is an enabling characteristic of cancer, a leading cause of death and disease worldwide.

Cells have developed highly sophisticated and complex mechanisms, collectively referred to as the DNA Damage Response (DDR), that detect and repair DNA damage. The DDR suppresses tumorigenesis and modulates the response to cancer therapies by conferring exploitable vulnerabilities to tumor cells. The targeting of the DDR, which protects against genomic instability, has proven to be an effective strategy for counteracting cancer development and improving therapy. Consequently, it is crucial to comprehensively study the fundamental mechanisms regulating the DDR under physiological and pathological conditions in order to develop targeted therapeutic strategies. The lab aims to leverage the DDR to better understand cancer development and to enhance therapy.

Recent advances in genome editing technologies enable the interrogation of encoded regulatory information with single-base resolution. This provides new opportunities for the development of a range of approaches to elucidating the fundamental molecular mechanisms underlying cancer progression and to enhance the efficiency of DNA damage-based cancer treatments. Deciphering the regulatory mechanisms that maintain genome stability is crucial not only for allowing new insights into the cellular response to conventional cancer therapies but also for developing new strategies to facilitate drug discovery.
 

More information on our research projects and recent publications on these topics can be found here: https://www.billonlab.com/researchprojects