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K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis

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  • Xiao-Lan Zhang

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Xin-Hui Chen

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Binwu Xu

    (the Second Affiliated Hospital of Nanchang University)

  • Min Chen

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Song Zhu

    (the Third Affiliated Hospital of Guangzhou Medical University
    The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital)

  • Nan Meng

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Ji-Zhong Wang

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Huifang Zhu

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • De Chen

    (the Third Affiliated Hospital of Guangzhou Medical University)

  • Jin-Bao Liu

    (Guangzhou Medical University)

  • Guang-Rong Yan

    (the Third Affiliated Hospital of Guangzhou Medical University)

Abstract

N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6A mRNA by ALKBH5, thereby promoting m6A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m6A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m6A demethylase activity and oncogenic roles of ALKBH5.

Suggested Citation

  • Xiao-Lan Zhang & Xin-Hui Chen & Binwu Xu & Min Chen & Song Zhu & Nan Meng & Ji-Zhong Wang & Huifang Zhu & De Chen & Jin-Bao Liu & Guang-Rong Yan, 2023. "K235 acetylation couples with PSPC1 to regulate the m6A demethylation activity of ALKBH5 and tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39414-4
    DOI: 10.1038/s41467-023-39414-4
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    References listed on IDEAS

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    1. Nian Liu & Qing Dai & Guanqun Zheng & Chuan He & Marc Parisien & Tao Pan, 2015. "N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions," Nature, Nature, vol. 518(7540), pages 560-564, February.
    2. Xiao Wang & Zhike Lu & Adrian Gomez & Gary C. Hon & Yanan Yue & Dali Han & Ye Fu & Marc Parisien & Qing Dai & Guifang Jia & Bing Ren & Tao Pan & Chuan He, 2014. "N6-methyladenosine-dependent regulation of messenger RNA stability," Nature, Nature, vol. 505(7481), pages 117-120, January.
    3. Song Zhu & Ji-Zhong Wang & De Chen & Yu-Tian He & Nan Meng & Min Chen & Rui-Xun Lu & Xin-Hui Chen & Xiao-Lan Zhang & Guang-Rong Yan, 2020. "An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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