Keeping the genome stable is a daunting task because each cell in the human body receives an average of 10,000 DNA lesions every day. DNA damages can be spontaneously created during cellular metabolisms such as DNA replication or can be generated by environmental sources such as UV irradiation (Sunlight) or chemical agents (Smoking or chemotherapy drugs). Cells developed many different DNA repair pathways to fix every specific type of DNA lesions protecting the cells against an accumulation of DNA mutations and cell death. To coordinate all the repair operation, three checkpoint kinases ATR, ATM, and DNA-PKcs are activated by DNA damage and determine which processes in the cells have to be turned on in order to repair the DNA.

DNA damage Fig

Elucidate how cells detect DNA damage and promote DNA repair

The master checkpoint kinase ATR is the key DNA damage sensor during DNA replication and DNA repair. ATR activation leads to phosphorylation of hundreds of proteins involved in DNA damage signaling, DNA repair, cell cycle regulation, and cell death. When the function of ATR is compromised, the genome becomes extremely fragile, underscoring the crucial role of ATR in DNA replication and repair. Compromised ATR function is implicated in diseases such as the Seckel syndrome, Fanconi Anemia, and cancers. Nevertheless, a complete loss of ATR is not found in cancers, indicating that residual ATR function may be indispensable for cell survival.

Figure ATR signaling
Activation of the ATR pathway at stalled DNA replication forks caused by UV-induced lesion

Recently, pharmaceutical companies developed specific inhibitors against ATR. Treatment of cancer cells with ATR inhibitors leads to an extreme sensitivity of these cells to drugs that induce DNA damage implying the use of these inhibitors to treat patients with cancer. Our previous studies identified molecular mechanisms to explain why cancers are sensitive to ATR inhibitors (Buisson et al. Molecular Cell, 2015; Buisson et al. Molecular Cell, 2017; Buisson et al. Cancer Research, 2017 and Kabeche et al. Science, 2018). The laboratory focus to discover new pathways regulated by ATR, as well as identify new drugs and drug combinations to treat tumors in a targeted way that can be translated directly to clinical use.

Understand how DNA double-strand breaks are repaired

DNA double-strand breaks (DSB) are the most toxic lesions for cells and needs to be repaired quickly to avoid cell death. BRCA1, PALB2 and BRCA2 proteins are master players for DSB repair in human cells. Mutations in BRCA1, PALB2, and BRCA2 have been associated with genetic predisposition to ovarian, pancreatic and breast cancer. According to recent studies, 30-40% of women who inherit a harmful BRCA1, BRCA2 or PALB2 mutations will develop breast or ovarian cancer by age of 70.

Figure 1
Repair of a DNA double-strand break by Homologous Recombination.

Homologous recombination (HR) is the major double-strand DNA repair pathway during late S- and G2-phases of the cell cycle. By using the sister chromatid as a template, HR allows the faithful recovery of genetic information. A key step in HR is the formation of a RAD51 nucleoprotein filament around the single strand DNA. Our previous work identified BRCA1-PALB2-BRCA2 complex as essential to promote the localization and the formation of RAD51 filament at the DNA double-strand breaks and the repair. Furthermore, we showed that similar to BRCA1 and BRCA2-deficient cells, cancer cells deficient for PALB2 are extremely sensitive to PARP inhibitor suggesting the potential use of PARP inhibitors as treatment of breast cancer patients carrying PALB2 mutations (Buisson et al. Nature Structural & Molecular Biology, 2010; Buisson et al, Nucleic Acids Research, 2012; Buisson et al. Cell reports, 2014 and Buisson et al. Molecular Cell, 2017). The laboratory is focusing to better understand the function of the BRCA1-PALB2-BRCA2 complex and how to treat patients with breast and ovarian cancer caused by mutations in this complex.

Develop new strategies to target cancer cells.

Two homologous proteins, APOBEC3A (A3A) and APOBEC3B (A3B) have recently emerged as major drivers of mutation in cancer by directly attacking genomic DNA. By their unique ability to rewrite genomic information, understanding the function and regulation of A3A and A3B is crucial in resolving the fundamental mechanism behind how cancer cells accumulate mutations, increase genomic instability and developed resistance to current therapies. We recently discovered that A3A and A3B-expressing cells are exclusively sensitive to ATR inhibitors (Buisson et al. Cancer Research, 2017). Our results suggest that the use of ATR inhibitors may be a promising strategy to target and kill A3A and A3B-expressing cancer cells in patients. This discovery prompts a wealth of new exciting questions that we will be studied in the laboratory.

Figure APOBEC copie
APOBEC targets single-strand DNA and catalyzes the deamination of Cytosine to Uracil (Swanton et al. Cancer Discovery, 2015)