Decapping and exoribonuclease protein (DXO) is a multifunctional protein involved in mRNA quality control mechanisms. DXO, also known as Rai1/Ydr370c and Dom3Z in fungal species and mammals, plays a crucial role in the surveillance and maintenance of mRNA integrity during synthesis. It exhibits several biochemical functions, including decapping, pyrophosphohydrolase, deNADding, and 5′–3′ exoribonuclease activities [1]. DXO serves as a quality control factor to eliminate aberrantly capped transcripts and acts as a decapping enzyme, involved in the removal of incomplete 5′ cap structures [2]. Furthermore, DXO possesses pyrophosphohydrolase, decapping, and 5′-3′ exoribonuclease activities, enabling it to preferentially degrade incompletely 7-methylguanosine (m7G) capped or NAD+ capped mRNAs from the 5′ end [3]. Studies have shown that DXO can single-handedly decap and degrade mRNAs, distinguishing it from other classical decapping enzymes [4]. Additionally, DXO has been implicated in the turnover of NAD+-capped RNAs in mammalian cells, further highlighting its role in mRNA decay [5].
The DXO family of proteins, including DXO1, has been identified as non-canonical decapping enzymes that remove the entire cap structure of capped or incompletely capped RNA, indicating their significance in maintaining mRNA integrity [6]. Furthermore, DXO proteins in yeast and mammals have been found to hydrolyze the G cap and the m7G cap, and some have been discovered to decap the NAD cap (deNADding) [7]. Mutagenesis studies have indicated that the single active site of Rai1 and its homologues is responsible for all three activities: decapping, pyrophosphatase, and 5'-3' exoribonuclease, underscoring the multifunctional nature of DXO proteins [8].
References:
[1] J. Chang, X. Jiao, K. Chiba, C. Oh, C. Martin, M. Kiledjianet al., "Dxo1 is a new type of eukaryotic enzyme with both decapping and 5′-3′ exoribonuclease activity", Nature Structural & Molecular Biology, vol. 19, no. 10, p. 1011-1017, 2012. https://doi.org/10.1038/nsmb.2381
[2] B. Lu, Y. Yin, Y. Zhang, P. Guo, W. Li, & K. Liu, "Upregulation of npl4 promotes bladder cancer cell proliferation by inhibiting dxo destabilization of cyclin d1 mrna", Cancer Cell International, vol. 19, no. 1, 2019. https://doi.org/10.1186/s12935-019-0874-2
[3] D. Zhou, M. Lai, A. Luo, & C. Yu, "An rna metabolism and surveillance quartet in the major histocompatibility complex", Cells, vol. 8, no. 9, p. 1008, 2019. https://doi.org/10.3390/cells8091008
[4] X. Jiao, S. Doamekpor, J. Bird, B. Nickels, L. Tong, R. Hartet al., "5′ end nicotinamide adenine dinucleotide cap in human cells promotes rna decay through dxo-mediated denadding", Cell, vol. 168, no. 6, p. 1015-1027.e10, 2017. https://doi.org/10.1016/j.cell.2017.02.019
[5] M. Kiledjian, "Eukaryotic rna 5′-end nad + capping and denadding", Trends in Cell Biology, vol. 28, no. 6, p. 454-464, 2018. https://doi.org/10.1016/j.tcb.2018.02.005
[6] X. Chen, K. Li, J. Hua, H. Zhao, F. Zhang, Q. Liet al., "Arabidopsis dxo1 activates rnmt1 to methylate the mrna guanosine cap", Nature Communications, vol. 14, no. 1, 2023. https://doi.org/10.1038/s41467-023-35903-8
[7] L. Zhai and S. Xiang, "Mrna quality control at the 5’ end", Journal of Zhejiang University Science B, vol. 15, no. 5, p. 438-443, 2014. https://doi.org/10.1631/jzus.b1400070
[8] K. Drążkowska, R. Tomecki, M. Warmiński, N. Baran, D. Cysewski, A. Depaixet al., "2′-o-methylation of the second transcribed nucleotide within the mrna 5′ cap impacts the protein production level in a cell-specific manner and contributes to rna immune evasion", Nucleic Acids Research, vol. 50, no. 16, p. 9051-9071, 2022. https://doi.org/10.1093/nar/gkac722
