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

Nicola P. Montaldo, Diana L. Bordin, Alessandro Brambilla, Marcel Rösinger, Sarah L. Fordyce Martin, Karine Øian Bjørås, Stefano Bradamante, Per Arne Aas, Antonia Furrer, Lene C. Olsen, Nicolas Kunath, Marit Otterlei, Pål Sætrom, Magnar Bjørås, Leona D. Samson and Barbara van Loon ()
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Nicola P. Montaldo: Norwegian University of Science and Technology (NTNU)
Diana L. Bordin: Norwegian University of Science and Technology (NTNU)
Alessandro Brambilla: Norwegian University of Science and Technology (NTNU)
Marcel Rösinger: University of Zurich
Sarah L. Fordyce Martin: Norwegian University of Science and Technology (NTNU)
Karine Øian Bjørås: Norwegian University of Science and Technology (NTNU)
Stefano Bradamante: Norwegian University of Science and Technology (NTNU)
Per Arne Aas: Norwegian University of Science and Technology (NTNU)
Antonia Furrer: University of Zurich
Lene C. Olsen: Norwegian University of Science and Technology (NTNU)
Nicolas Kunath: Norwegian University of Science and Technology (NTNU)
Marit Otterlei: Norwegian University of Science and Technology (NTNU)
Pål Sætrom: Norwegian University of Science and Technology (NTNU)
Magnar Bjørås: Norwegian University of Science and Technology (NTNU)
Leona D. Samson: David H. Koch Institute of integrative Cancer Research, Massachusetts Institute of Technology
Barbara van Loon: Norwegian University of Science and Technology (NTNU)

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13394-w

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