Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.
Department of Molecular Mechanisms of Disease, University of Zurich, 8057, Zurich, Switzerland.
Nat Commun. 2019 Nov 29;10(1):5460. 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.
碱基切除修复（BER）由烷基腺嘌呤 DNA 糖基化酶（AAG）启动，对于去除异常甲基化的 DNA 碱基至关重要。基因组不稳定性和异常碱基的积累伴随着多种疾病，包括癌症和神经紊乱。虽然 BER 在裸露 DNA 上的研究已经很深入，但 BER 在染色质上如何有效地发挥作用仍不清楚。在这里，我们表明 AAG 与染色质结合，并与 RNA 聚合酶（pol）II 形成复合物。这是通过与延伸因子（Elongator）的直接相互作用实现的，导致转录的共调控。重要的是，在共调控的基因中，异常甲基化的碱基在富含 BER 酶 AAG 和 APE1、延伸因子和活性 RNA pol II 的区域中朝向 3' 端积累。活性转录和功能性延伸因子对于确保有效的 BER 进一步至关重要，通过促进 AAG 和 APE1 染色质募集来实现。我们的研究结果为活跃转录的染色质中基因组稳定性的维持提供了新的认识，并揭示了异常甲基化碱基在基因表达调控中的作用。
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