{"title":"YTHDF3识别DNA n6 -甲基腺嘌呤并招募ALKBH1从基因组DNA中去除6mA。","authors":"Xin-Hui Chen, Zi-Lu Wang, Jincui Yang, Min Chen, Si-Yi Zhao, Kun-Xiong Guo, Xuelong Zheng, Zhengwei Zhao, Xiaoqiang Chen, Jing Li, Min-Min Zhang, Ling Ran, Huifang Zhu, Xiao-Feng Gu, Guang-Rong Yan","doi":"10.1038/s44318-025-00512-2","DOIUrl":null,"url":null,"abstract":"<p><p>DNA N<sup>6</sup>-methyladenine (6mA) is an emerging epigenetic mark in the mammalian genome. ALKBH1 preferentially exhibits 6mA demethylase activity for single-stranded DNA (ssDNA) or bubbled/bulged DNA, but not for double-stranded DNA (dsDNA). Nevertheless, ALKBH1 significantly decreases the cellular 6mA level in genomic DNA, whose prevailing DNA conformation in living mammalian cells is dsDNA. Therefore, the demethylase activity of ALKBH1 toward 6mA in genomic DNA, especially dsDNA, remains largely debated. Here, we found that YTHDF3 increases the 6mA demethylase activity of ALKBH1 in genomic DNA with different conformations, including dsDNA. Compared with ALKBH1, YTHDF3 preferentially recognizes and binds to 6mA-modified DNA with different conformations. YTHDF3 recognizes 6mA in genomic DNA, and binds ALKBH1 to recruit it to sites near 6mA in genomic DNA, thereby facilitating the ALKBH1-mediated removal of 6mA in genomic dsDNA. In summary, YTHDF3 is a novel genomic DNA reader and guides ALKBH1 to remove 6mA in human genomic DNA.</p>","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"4899-4917"},"PeriodicalIF":8.3000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402098/pdf/","citationCount":"0","resultStr":"{\"title\":\"YTHDF3 recognizes DNA N6-methyladenine and recruits ALKBH1 for 6mA removal from genomic DNA.\",\"authors\":\"Xin-Hui Chen, Zi-Lu Wang, Jincui Yang, Min Chen, Si-Yi Zhao, Kun-Xiong Guo, Xuelong Zheng, Zhengwei Zhao, Xiaoqiang Chen, Jing Li, Min-Min Zhang, Ling Ran, Huifang Zhu, Xiao-Feng Gu, Guang-Rong Yan\",\"doi\":\"10.1038/s44318-025-00512-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>DNA N<sup>6</sup>-methyladenine (6mA) is an emerging epigenetic mark in the mammalian genome. ALKBH1 preferentially exhibits 6mA demethylase activity for single-stranded DNA (ssDNA) or bubbled/bulged DNA, but not for double-stranded DNA (dsDNA). Nevertheless, ALKBH1 significantly decreases the cellular 6mA level in genomic DNA, whose prevailing DNA conformation in living mammalian cells is dsDNA. Therefore, the demethylase activity of ALKBH1 toward 6mA in genomic DNA, especially dsDNA, remains largely debated. Here, we found that YTHDF3 increases the 6mA demethylase activity of ALKBH1 in genomic DNA with different conformations, including dsDNA. Compared with ALKBH1, YTHDF3 preferentially recognizes and binds to 6mA-modified DNA with different conformations. YTHDF3 recognizes 6mA in genomic DNA, and binds ALKBH1 to recruit it to sites near 6mA in genomic DNA, thereby facilitating the ALKBH1-mediated removal of 6mA in genomic dsDNA. In summary, YTHDF3 is a novel genomic DNA reader and guides ALKBH1 to remove 6mA in human genomic DNA.</p>\",\"PeriodicalId\":50533,\"journal\":{\"name\":\"EMBO Journal\",\"volume\":\" \",\"pages\":\"4899-4917\"},\"PeriodicalIF\":8.3000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402098/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EMBO Journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s44318-025-00512-2\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/25 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Journal","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44318-025-00512-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/25 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
DNA n6 -甲基腺嘌呤（n6 - methylladenine, 6mA）是哺乳动物基因组中一种新兴的表观遗传标记。ALKBH1对单链DNA （ssDNA）或泡状/膨化DNA优先表现出6mA的去甲基化酶活性，而对双链DNA （dsDNA）则没有。然而，ALKBH1显著降低了基因组DNA中的细胞6mA水平，而在哺乳动物细胞中，基因组DNA的主要构象是dsDNA。因此，ALKBH1对基因组DNA，特别是dsDNA中6mA的去甲基化酶活性仍然存在很大争议。在这里，我们发现YTHDF3增加了包括dsDNA在内的不同构象的基因组DNA中ALKBH1的6mA去甲基化酶活性。与ALKBH1相比，YTHDF3优先识别并结合不同构象的6ma修饰DNA。YTHDF3识别基因组DNA中的6mA，并结合ALKBH1将其招募到基因组DNA中6mA附近的位点，从而促进ALKBH1介导的基因组dsDNA中6mA的去除。综上所述，YTHDF3是一种新型的基因组DNA读取器，可引导ALKBH1去除人类基因组DNA中的6mA。
YTHDF3 recognizes DNA N6-methyladenine and recruits ALKBH1 for 6mA removal from genomic DNA.
DNA N6-methyladenine (6mA) is an emerging epigenetic mark in the mammalian genome. ALKBH1 preferentially exhibits 6mA demethylase activity for single-stranded DNA (ssDNA) or bubbled/bulged DNA, but not for double-stranded DNA (dsDNA). Nevertheless, ALKBH1 significantly decreases the cellular 6mA level in genomic DNA, whose prevailing DNA conformation in living mammalian cells is dsDNA. Therefore, the demethylase activity of ALKBH1 toward 6mA in genomic DNA, especially dsDNA, remains largely debated. Here, we found that YTHDF3 increases the 6mA demethylase activity of ALKBH1 in genomic DNA with different conformations, including dsDNA. Compared with ALKBH1, YTHDF3 preferentially recognizes and binds to 6mA-modified DNA with different conformations. YTHDF3 recognizes 6mA in genomic DNA, and binds ALKBH1 to recruit it to sites near 6mA in genomic DNA, thereby facilitating the ALKBH1-mediated removal of 6mA in genomic dsDNA. In summary, YTHDF3 is a novel genomic DNA reader and guides ALKBH1 to remove 6mA in human genomic DNA.
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