Interplay between the transcription machinery and the responses to DNA damage and replication stress

Abstract

Human cells are continuously threatened by DNA damage from endogenous sources such as replication stress. To face this threat and prevent cancer, intracellular signaling pathways that promote DNA repair, collectively known as the DNA damage response, have evolved. On the other hand, radiotherapy and several types of chemotherapy kill cancer cells by inducing DNA damage. DNA repair can counteract cell death after such treatments. The DNA damage response is thus very important for cancer progression and treatment. The transcription machinery is emerging as a new and central factor in the DNA damage response. In this thesis, Bay and colleagues aimed to understand the interplay between the transcription machinery and the responses to DNA damage and replication stress. Transcription and DNA replication may collide as they share the same template, but how the transcription machinery is regulated to prevent such collisions has remained unclear. By studying the chromatin stability of RNA polymerase II (RNAPII), the main mediator of transcription, Bay and colleagues found a new mechanism to prevent such collisions. To address how RNAPII is affected by DNA damage, Bay and colleagues developed a new flow cytometry technique. Using it, they gained novel insight into the regulation of the transcription cycle with and without DNA damage. RNAPII may directly play a role in the DNA damage response by promoting DNA repair. To address this, Bay and colleagues manipulated the phosphorylation levels of RNAPII. They found that phosphorylation of RNAPII promotes binding of several DNA repair factors and likely enhances DNA repair via non-homologous end-joining. Altogether, the work of this thesis provides new knowledge regarding the interplay between the transcription machinery and the responses to DNA damage and replication stress. Such knowledge provides important insights that may be exploited in cancer treatment in the future.