The interplay between DNA damage and transcription

DNA damages compromise the ability of the genome to function. Cells from all organisms have mechanisms to recognize DNA damage, initiate a signaling response, and recruit repair enzymes. Complete failure of these mechanisms leads to cell death. Incorrect or inefficient repair leads to mutations and cancer. Our work focuses on damages that distort the DNA helix, specifically the carcinogenic dimers induced by ultraviolet (UV) radiation, and the bulky DNA adducts induced by cigarette smoke and the chemotherapy drug cisplatin [Cis-diamminedichloroplatinum(II)].

There is a complex relationship between helix-distorting damages and transcription. These damages block RNA polymerases, and at the same time induce a transcriptional stress response. In parallel, active transcription enhances the ability to recognize and repair damages. To study the intertwined relationship between DNA damage and transcription, we utilize genomic methods for mapping DNA damages and DNA repair at single nucleotide resolution, in parallel to transcription, across the human genome. The genomic methods characterize transcription coupled repair at an unprecedented level. Damage levels are dictated primarily by sequence composition, and revealed asymmetrical nucleotide distributions in transcribed regions. In turn, nucleotide composition and gene architecture are major determinants of the transcriptional response to damage. These and other findings frame the transcriptional response to damage first as a direct mechanism for damage detection, and second, as a hard-wired response in cis, rather than a response regulated solely by trans-acting transcription factors.