YTHDF3 recognizes DNA N6-methyladenine and recruits ALKBH1 for 6mA removal from genomic DNA
文献类型： 外文期刊
作者： Chen, Xin-Hui 1 ; Wang, Zi-Lu 1 ; Yang, Jincui 1 ; Chen, Min 1 ; Zhao, Si-Yi 1 ; Guo, Kun-Xiong 1 ; Zheng, Xuelong 1 ; Zhao, Zhengwei 1 ; Chen, Xiaoqiang 1 ; Li, Jing 1 ; Zhang, Min-Min 1 ; Ran, Ling 1 ; Zhu, Huifang 1 ; Gu, Xiao-Feng 2 ; Yan, Guang-Rong 1 ;
作者机构： 1.Guangzhou Med Univ, Affiliated Hosp 3, Biomed Res Ctr,Guangdong Prov Key Lab Major Obstet, Guangdong Prov Clin Res Ctr Obstet & Gynecol, Guangzhou 510150, Peoples R China
2.Chinese Acad Agr Sci, Biotechnol Res Inst, Beijing 100081, Peoples R China
关键词： Genomic DNA 6mA; ALKBH1; Genomic 6mA Reader; YTHDF3; dsDNA
期刊名称：EMBO JOURNAL （ 影响因子：8.3； 五年影响因子：10.6 ）
ISSN： 0261-4189
年卷期： 2025 年 44 卷 17 期
页码：
收录情况： SCI
摘要： 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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