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Nat Commun. 2019 Nov 29;10(1):5460. doi: 10.1038/s41467-019-13394-w.

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

Author information

1
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
2
Department of Molecular Mechanisms of Disease, University of Zurich, 8057, Zurich, Switzerland.
3
Paul Scherrer Institute, 5232, Villigen, Switzerland.
4
Bioinformatics core facility - BioCore, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
5
K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
6
Department of Computer Science, Faculty of Information Technology and Electrical Engineering, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
7
Department of Microbiology, Oslo University Hospital, University of Oslo, 0372, Oslo, Norway.
8
Department of Biological Engineering, Department of Biology, David H. Koch Institute of integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
9
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway. barbara.v.loon@ntnu.no.
10
Department of Molecular Mechanisms of Disease, University of Zurich, 8057, Zurich, Switzerland. barbara.v.loon@ntnu.no.

Abstract

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.

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