Coupling between nucleotide excision repair and gene expression

Abstract

Gene expression and DNA repair are fundamental processes for life. During the last decade, accumulating experimental evidence point towards different modes of coupling between these processes. Here we discuss the molecular mechanisms by which RNAPII-dependent transcription affects repair by the Nucleotide Excision Repair system (NER) and how NER activity, through the generation of single stranded DNA intermediates and activation of the DNA damage response kinase ATR, drives gene expression in a genotoxic scenario. Since NER-dependent repair is compromised in Xeroderma Pigmentosum (XP) patients, and having in mind that these patients present a high degree of clinical heterogeneity, we speculate that some of the clinical features of XP patients can be explained by misregulation of gene expression.

Keywords: Gene expression; Nucleotide Excision Repair; UV light; Xeroderma Pigmentosum.

Figure 1.

Different modes of coupling between Nucleotide Excision Repair and Gene Expression. A. Common factors shared by transcription and DNA repair: Apart from the well documented roles of TFIIH and its helicases subunits XPB and XPD, other NER factors such as XPC, XPA, XPF and XPG showed to be recruited to promoters of inducible genes in the absence of exogenous genotoxic attack. B. RNAPII as a DNA damage sensor: In TC-NER a stalled RNAPII in front of a lesion serves as a DNA damage sensor favoring the recruitment of NER factors and hence the preferential repair of template strand in actively transcribed genes. C. DNA Repair as a driver for gene expression: RNAPII is the target of a signaling cascade initiated by repair. ssDNA generated during repair activates ATR that in turn regulates RNAPII CTD phosphorylation status therefore affecting transcriptional properties, such as elongation rates, and hence gene expression patterns. Different mutations in NER effector factors could lead to different levels of ssDNA exposure and ATR activation.