Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis

Abstract

Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards understanding the molecular basis of RNA polymerase II (Pol II) transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. In particular, we will focus on the three key checkpoint steps of controlling Pol II transcriptional fidelity: insertion (specific nucleotide selection and incorporation), extension (differentiation of RNA transcript extension of a matched over mismatched 3'-RNA terminus), and proofreading (preferential removal of misincorporated nucleotides from the 3'-RNA end). We will also discuss some novel insights into the molecular basis and chemical perspectives of controlling Pol II transcriptional fidelity through structural, computational, and chemical biology approaches.

Keywords: Chemical biology; Computational biology; DNA damage recognition; Fidelity control; Nonpolar isostere; RNA polymerase II; Structural biology; Synthetic nucleotide analogs; Transcription elongation; Transcriptional lesion bypass; Unlocked nucleic acid.