Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6

作者：Lulu Ma, Hongyun Lu, Zizi Tian, Meiting Yang, Jun Ma, Guohui Shang, Yunlong Liu, Mengjia Xie, Guoguo Wang, Wei Wu, Ziding Zhang, Shaodong Dai, Zhongzhou Chen · 发表于：Journal of Biological Chemistry · 年份：2022 · DOI：10.1016/j.jbc.2022.101671 · 被引用次数：24 · 研究领域：RNA modifications and cancer、RNA Research and Splicing、Biochemical and Molecular Research

Human AlkB homolog 6, ALKBH6, plays key roles in nucleic acid damage repair and tumor therapy. However, no precise structural and functional information are available for this protein. In this study, we determined atomic resolution crystal structures of human holo-ALKBH6 and its complex with ligands. AlkB members bind nucleic acids by NRLs (nucleotide recognition lids, also called Flips), which can recognize DNA/RNA and flip methylated lesions. We found that ALKBH6 has unusual Flip1 and Flip2 domains, distinct from other AlkB family members both in sequence and conformation. Moreover, we show that its unique Flip3 domain has multiple unreported functions, such as discriminating against double-stranded nucleic acids, blocking the active center, binding other proteins, and in suppressing tumor growth. Structural analyses and substrate screening reveal how ALKBH6 discriminates between different types of nucleic acids and may also function as a nucleic acid demethylase. Structure-based interacting partner screening not only uncovered an unidentified interaction of transcription repressor ZMYND11 and ALKBH6 in tumor suppression but also revealed cross talk between histone modification and nucleic acid modification in epigenetic regulation. Taken together, these results shed light on the molecular mechanism underlying ALKBH6-associated nucleic acid damage repair and tumor therapy.