Project: Transcriptional mutagenesis and cellular effects
Frequently occurring non-bulky lesions, such as 8-oxoguanine (8oxoG), and O6-methylguanine (O6meG), are efficiently bypassed by RNA polymerases in vitro. This could induce incorporation of incorrect bases into nascent RNA, potentially altering the transcripts function via a process called transcriptional mutagenesis (TM). Recent studies have reported the ability of 8oxoG and O6meG to induce TM in mammalian cells affecting protein functions. However, the relative importance of TM in human health is still virtually untouched.
The potentially detrimental biological outcomes of TM, leading to a pool of mutant proteins, include a number of events such as deregulated cell death and changes in cellular physiology. Even though the impact of DNA damage on transcription is severe, our knowledge in this area in human cells is poor at many levels, including (i) how defective transcripts originating from TM alter protein function, (ii) what effects expression of these altered proteins has on cells, and (iii) how the cellular signaling events in response to cellular stress are affected in the presence of TM proteins. In order to characterize each of these events, an approach has been developed for studying the potentially detrimental cellular effects originating from p53 TM. We are furthermore investigating the potential effects of TM on splicing fidelity.
The project is performed in collaboration with Professor David Scicchitanos group at Department of Biology, New York University.
- Seventh framework program Marie Curie international reintegration grant (IRG)
- Swedish Research Council (VR)
- Carl Tryggers Foundation
Transcriptional mutagenesis reduces splicing fidelity in mammalian cells.
Nucleic Acids Res. 2017 Jun;45(11):6520-6529
Transcriptional mutagenesis: p53 protein as probe of biological effects.
Dreij K, Malvezzi S, Burns J, Scicchitano DA, Stenius U
Toxicol. Lett. 2012 June;211(Suppl):S68-S69
O6-methylguanine induces altered proteins at the level of transcription in human cells.
Nucleic Acids Res. 2010 Dec;38(22):8178-87
DNA damage and transcription elongation: consequences and RNA Integrity.
Dreij K, Burns J, Dimitri A, Nirenstein L, Noujnykh T, Scicchitano DA
In The Chemical Biology of DNA Damage. N. Geacintov, S. Broyde, eds. Wiley-VCH Verlag, Weinhem. Chapter 17, 399-437. 2010.