Grant: Travel Awards - Institute Community Support

Human cells experience DNA damage daily, but DNA repair systems maintain extremely low mutation rates. By contrast, many cancer cells accumulate thousands of mutations, including mutations to the DNA repair pathways themselves. Understanding the function of DNA repair pathways in cancer will aid the development of new therapies. New studies suggest that a protein named CDK12 is a regulator of DNA repair. There are CDK12 mutations in many tumours, especially from subtypes of breast and ovarian cancers that typically have poor patient outcomes. In both breast and ovarian cancer cells, we found that CDK12 regulates an essential cellular process termed "alternative splicing," where gene segments are assembled in different combinations to create different functional versions of the protein. Through alternative splicing, we found that CDK12 controls a protein called ATM, a key master switch of DNA repair that is often dysfunctional in tumour cells. CDK12 also controls a specific version of the DNAJB6 protein, which in turn promotes tumour-like behaviour of breast cancer cells. These observations reveal how errors in DNA repair processes regulated by CDK12 can lead to tumour development and define the population of cancers that can be treated with CDK12-based therapy.