Thabiso Shaun Ncube
ADP-ribosyl hydrolases in genome stability
To protect the genome from damage, organisms have evolved a cellular defence mechanism termed the DNA damage response (DDR). The DDR includes a diverse set of signal transduction pathways and effector proteins that act to sense DNA lesions and effectively repair the damage, limiting the propagation of genomic instability. Exploiting DDR pathways to specifically target and kill cancer cells has become an attractive therapeutic avenue within cancer research. This is exemplified by the synthetic lethal interaction between PARP inhibition and BRCA1 or BRCA2-deficient tumours.
Recent research suggests that inhibiting other targets in PARP-dependent pathways may be beneficial, in particular targeting the hydrolases that revert PARP-dependent protein modifications such as PARG or ARH3. However, compared to PARP transferases, much less is known about the function of the reversing enzymes. Therefore, understanding their molecular function and specificity within the DNA damage response mechanisms will be important.
How could your research ultimately benefit patients?
The research on novel regulators of ADP-ribosylation signalling will contribute to understanding the molecular mechanisms that regulate genome stability and the response to PARP inhibitors used in the clinics. In the longer term this research can provide a foundation for the discovery of novel mechanisms of therapeutic interventions and/or biomarkers of sensitivity/resistance to therapies by PARP inhibitors, allowing for improved patient stratification.
About Thabiso
In 2022, I obtained a BSc (Hons) degree in Applied Biology and Biochemistry from the National University of Science & Technology in Bulawayo, Zimbabwe where I conducted research on antibiotic resistance genes. Between late 2022 and 2024, I transitioned into the diagnostic laboratory environment, working as a scientist across the molecular biology and phlebotomy departments. Since then, I completed an MPhil in Genomic Medicine at the University of Cambridge.
Fundamentally, I am driven by scientific curiosity, specifically in genetics and the potential of human genomic research in healthcare. My prior experiences, in particular within the medical field, motivated me to pursue cancer-related research, which later developed into an interest in cancer genomics. Currently, I am interested in understanding the genomic complexities that influence treatment responsiveness and the mechanistic underpinnings in DNA damage responses in cancer cells.