Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression

• Published in: Nature communications 2019-11, Vol.10 (1), p.5460-13, Article 5460
• Main Authors: Montaldo, Nicola P., Bordin, Diana L., Brambilla, Alessandro, Rösinger, Marcel, Fordyce Martin, Sarah L., Bjørås, Karine Øian, Bradamante, Stefano, Aas, Per Arne, Furrer, Antonia, Olsen, Lene C., Kunath, Nicolas, Otterlei, Marit, Sætrom, Pål, Bjørås, Magnar, Samson, Leona D., van Loon, Barbara
• Format: Article
• Language: English
• Subjects: 13/109; 13/44; 13/51; 14/19; 38/15; 38/22; 38/77; 38/90; 38/91; 631/337/1427/1429; 631/45/147; 82/1; 82/16; 82/29; 82/58; 82/80; 82/83; Aberration; Base excision repair; Chromatin; Chromatin - genetics; Chromatin - metabolism; Deoxyribonucleic acid; DNA; DNA glycosylase; DNA Glycosylases - metabolism; DNA Methylation; DNA repair; DNA Repair - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; DNA-directed RNA polymerase; Elongation; Gene Expression; Gene Expression Regulation - genetics; Gene regulation; Genomes; Genomic Instability; HEK293 Cells; Humanities and Social Sciences; Humans; Maintenance; multidisciplinary; Neurological diseases; Repair; Ribonucleic acid; RNA; RNA polymerase; RNA polymerase II; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Science; Science (multidisciplinary); Transcription elongation; Transcription Elongation, Genetic; Transcriptional Elongation Factors - genetics; Transcriptional Elongation Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13394-w

Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression. How genome stability is maintained at regions of active transcription is currently not entirely clear. Here, the authors reveal an association between base excision repair factors and transcription elongation to modulate DNA repair.