Abstract:

Exonuclease EXO1 performs multiple roles in DNA replication and DNA damage repair (DDR). However, EXO1 loss is well-tolerated, suggesting the existence of compensatory mechanisms that could be exploited in DDR-deficient cancers. Using CRISPR screening, we find EXO1 loss as synthetic lethal with many DDR genes somatically inactivated in cancers, including Fanconi Anaemia (FA) pathway and BRCA1-A complex genes. We also identify the spliceosome factor and tumour suppressor ZRSR2 as synthetic lethal with loss of EXO1 and show that ZRSR2-deficient cells are attenuated for FA-pathway activation, exhibiting cisplatin sensitivity and radial chromosome formation, which we attribute to discreet splicing defects that compromise FA pathway genes. Finally, FA or ZRSR2 deficiencies depend on EXO1 nuclease activity and can be potentiated in combination with PARP inhibitors or ionizing radiation. These findings implicate EXO1 as a synthetic lethal vulnerability and promising drug target in a broad spectrum of DDR-deficient cancers unaddressed by current therapies.

Bio:

Marija is originally from Zagreb, Croatia, where she obtained her Diploma/MSc in Molecular Biology from the University of Zagreb. Marija did her PhD in the lab of Professor Karim Labib, starting at the Cancer Research UK Manchester Institute and moving with Karim’s lab to MRC PPU in the final year of her PhD. Marija’s PhD thesis was on the mechanism of CMG disassembly at the end of chromosome replication and identifying Cdc48/p97 as the factor driving the disassembly. For her PhD work Marija won the Cancer Research UK Pontecorvo Prize and University of Dundee’s Howard Elder Prize for Cancer Research. Marija then went to do her postdoc in the lab of Simon Boulton at The Francis Crick Institute, where she has since worked on double strand break repair metabolism, telomere maintenance metabolism as well as investigation of DNA damage repair pathways in the context of cancer by using CRISPR screening approaches. Her main recent focus has been the genetics of exonuclease EXO1 and defining EXO1 as a promising cancer therapy target, and on which she has been continuing her work as Crick Early Career Translation Fellow.