Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 139, Issue 41, Pages 14436-14442Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.7b06381
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Funding
- National Institutes of Health [R01 GM102362, R01 HG006827]
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
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N-6-Methyladenine (N-6-mA or 6 mA) is an epigenetic DNA modification in eukaryotic genomes. In contrast to the well-established roles of 5-methylcytosine for epigenetic regulation of gene expression, the functional roles of N-6-mA remain elusive. In particular, the impact of N-6-mA modification of the DNA template on RNA polymerase II (pol II) transcription elongation is not known. In this work, using the Saccharomyces cerevisiae pol II transcriptional elongation system as a model, we investigated the molecular mechanism of pol II recognition and processing of N-6-mA sites via both biochemical and structural approaches. We found that N-6-mA causes site-specific pol II pausing/stalling. Structural analysis revealed that while N-6-mA can reach the +1 template position, the stability of the N-6-mA and UTP base pairing is compromised. Taken together, we reveal that the presence of the 6-methyl group on adenine reduces incorporation efficiency and promotes backtracking translocation. Our studies with yeast pol II provide molecular insights into understanding the impacts of N-6-mA on pol II transcription dynamics in different organisms.
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