DNA damage can induce mutations in RNA leading to impaired function of tumor suppressor proteins
A study by researchers at the Institute of Environmental Medicine, New York University and University of Manchester published in PNAS shows that presence of DNA damage on the transcribed strand of a gene can induce transcription errors and subsequent production of protein with altered functions which could contribute to disease development.
Frequently occurring DNA damage, such as 8-oxoguanine and O6-methylguanine, are efficiently bypassed by RNA polymerases during gene expression. This may result in incorporation of incorrect bases into RNA, potentially altering the transcript’s function via a process called transcriptional mutagenesis. Although the concept of transcriptional mutagenesis is established, the biological consequences are still not well studied. It is still unknown to which extent these transcriptional mutations occur in mammalian cells and the role they might play in disease processes.
The study, which was led by Kristian Dreij at the Institute of Environmental Medicine, Karolinska Institutet, investigated the impact of O6-methylguanine on transcription fidelity of p53 and the subsequent effects on the protein’s function as tumor suppressor in human cells. The results showed that transcriptional mutagenesis at codon 248 in only 15% of the transcripts leads to a reduced ability of p53 protein to transactivate several of its target genes, including CDKN1A (p21) and BBC3 (PUMA). This resulted in a reduced ability to arrest cells at the G1/S cell cycle checkpoint and an impaired activation of the intrinsic pathway of apoptosis, both canonical p53 tumor suppressor functions. Taken together, these studies show that reduced function of tumor suppressors due to transcriptional mutagenesis may well play an important role in allowing initiated cells to escape growth-inhibitory or apoptotic signals thus leading to additional tumor growth and aggressiveness.
The research was financed by grants from several bodies, including the Swedish Research Council, Carl Trygger’s foundation, a Marie Curie FP7 fellowship and the US National Institutes of Health (NIH).
O6-methylguanine–induced transcriptional mutagenesis reduces p53 tumor-suppressor function
Monika Ezerskyte, João A. Paredes, Stefano Malvezzi, John A. Burns, Geoffrey P. Margison, Magnus Olsson, David A. Scicchitano and Kristian Dreij
PNAS April 17, 2018.
Kristian Dreij, Institute of Environmental Medicine