Human cells experience DNA damage every day, but DNA repair systems ensure that resulting mutation rates are extremely low. Two main pathways repair severe DNA damage in cells. The 'copying' pathway connects broken DNA ends by copying the missing sequence from the second DNA copy that is present before cells divide. The 're-joining' pathway simply re-joins the broken DNA ends irrespective of the missing sequence. Mutations in these pathways are frequently found in cancer cells, which can accumulate thousands of mutations.
Recent studies show that tumours with mutations that inactivate the copying pathway can be effectively treated with drugs that inhibit the re-joining pathway. After drug treatment, both repair pathways are impaired in tumour cells, whereas normal cells still retain one functional pathway. As a result, doses can be adjusted so that side effects of chemotherapy are milder.
A protein named CDK12 appears to be a regulator of the copying pathway, and cells with abnormal CDK12 are sensitive to drugs that inhibit the re-joining pathway. Mutations in CDK12 have been found in many tumour types. Our preliminary results show that CDK12 regulates an essential cellular process termed 'alternative splicing,' where gene segments are assembled in different orders to create different versions of the same gene.
We will examine how CDK12 changes the alternative splicing of genes after DNA damage, and how this regulation is impaired by mutations in CDK12 that have been found in tumours. Ultimately, this work could lead to new research tools and help to define the population of cancers that can be treated with CDK12-based therapy.