HM/
Articles/
2603003303
  • Open Access
  • Article

Structural and Biochemical Analysis of Human Schlafen5 Reveals the Molecular Basis of Its Anti-Tumor Function

  • Jin-Yu Yang 1,2,*,†,   
  • Jun-Ying Ou 1,†,   
  • Meng Luo 1,†,   
  • Zi-Wen Wang 1,†,   
  • Yong-Qiang Zheng 1,   
  • Ze-Xian Liu 1,   
  • Song Gao 1,3,4,*

Received: 02 Dec 2025 | Revised: 25 Feb 2026 | Accepted: 12 Jul 2026 | Published: 10 Sep 2026

Abstract

Background: Schlafen5 (SLFN5) is an IFN-inducible member of the SLFN protein family involved in immune regulation, viral inhibition and tumor control. Recently, SLFN5 was suggested to inhibit the invasion of many kinds of malignant cells, and its expression positively correlates with the overall survival of relevant patients. However, the functional mechanism of SLFN5 remains elusive. Here, we aim to investigate the biochemical properties and anti-tumor mechanism of SLFN5. Methods: We expressed, purified and crystallized the N-terminal domain of human SLFN5 (hSLFN5-N) and solved its structure by molecular replacement. We examined the binding and digestion ability of hSLFN5-N to several kinds of nucleic acid substrates, including DNA, RNA, tRNA and rRNA via electrophoretic mobility shift assay (EMSA) and cleavage assay in vitro. Structure-based mutation screening and cancer-associated hot-spot single-point mutations in hSLFN5 were analyzed to reveal the critical amino acid sites that influence the structure, biochemical and physiological function of the protein. Results: Structurally, hSLFN5-N is characterized by a pseudo-dimeric domain organization with a flexible central valley that is narrower than that of rat (r)SLFN13-N. Unlike rSLFN13-N, hSLFN5-N is incapable of cleaving tRNA and rRNA, but it is able to bind DNA and cleave specific RNA substrates. Site-mutation analysis suggested that positively charged residues surrounding the central valley determine the DNA and RNA affinity of hSLFN5. Structure-based analysis revealed that cancer-associated mutations tend to severely affect the folding stability and function of SLFN5 by disrupting intra-/inter-molecular interactions, incurring unfavorable alterations in local conformation, or altering potential post-translational modifications (PTMs) of the wild-type protein. Besides, SLFN5 had no DNA sequence selectivity in A375 cells, which indicated that its anti-migration activity may mainly depend on its RNA manipulation ability rather than on its DNA affinity as a transcription factor. Conclusions: SLFN5 is a DNA- and RNA-binding protein with endonuclease activity on specific RNA substrates, which determines the role of SLFN5 as a tumor suppressor. Single-point mutations may disrupt the structural stability, RNA manipulation capacity and thus the tumor suppressor function of SLFN5.

Graphical Abstract

Image Viewer
Open in new tab
Download Image

References 

  • 1.

    Mavrommatis, E.; Fish, E.N.; Platanias, L.C. The Schlafen Family of Proteins and Their Regulation by Interferons. J. Interferon Cytokine Res. 2013, 33, 206–210. https://doi.org/10.1089/jir.2012.0133.

  • 2.

    Liu, F.; Zhou, P.; Wang, Q.; Zhang, M.; Li, D. The Schlafen Family: Complex Roles in Different Cell Types and Virus Replication. Cell Biol. Int. 2018, 42, 2–8. https://doi.org/10.1002/cbin.10778.

  • 3.

    Wu, X.; Schnitzler, G.R.; Gao, G.F.; Diamond, B.; Baker, A.R.; Kaplan, B.; Williamson, K.; Westlake, L.; Lorrey, S.; Lewis, T.A.; et al. Mechanistic Insights into Cancer Cell Killing through Interaction of Phosphodiesterase 3A and Schlafen Family Member 12. J. Biol. Chem. 2020, 295, 3431–3446. https://doi.org/10.1074/jbc.ra119.011191. Correction in J. Biol. Chem. 2020, 295, 16464–16467. https://doi.org/10.1074/jbc.AAC120.016548.

  • 4.

    Ai, Y.; He, H.; Chen, P.; Yan, B.; Zhang, W.; Ding, Z.; Li, D.; Chen, J.; Ma, Y.; Cao, Y.; et al. An Alkaloid Initiates Phosphodiesterase 3A-Schlafen 12 Dependent Apoptosis without Affecting the Phosphodiesterase Activity. Nat. Commun. 2020, 11, 3236. https://doi.org/10.1038/s41467-020-17052-4.

  • 5.

    Yue, T.; Zhan, X.; Zhang, D.; Jain, R.; Wang, K.W.; Choi, J.H.; Misawa, T.; Su, L.; Quan, J.; Hildebrand, S.; et al. SLFN2 Protection of tRNAs from Stress-Induced Cleavage Is Essential for T Cell–Mediated Immunity. Science 2021, 372, eaba4220. https://doi.org/10.1126/science.aba4220.

  • 6.

    Metzner, F.J.; Huber, E.; Hopfner, K.P.; Lammens, K. Structural and Biochemical Characterization of Human Schlafen 5. Nucleic Acids Res. 2022, 50, 1147–1161. https://doi.org/10.1093/nar/gkab1278.

  • 7.

    Kim, E.T.; Dybas, J.M.; Kulej, K.; Reyes, E.D.; Price, A.M.; Akhtar, L.N.; Orr, A.; Garcia, B.A.; Boutell, C.; Weitzman, M.D. Comparative Proteomics Identifies Schlafen 5 (SLFN5) as a Herpes Simplex Virus Restriction Factor that Suppresses Viral Transcription. Nat. Microbiol. 2021, 6, 234–245. https://doi.org/10.1038/s41564-020-00826-3.

  • 8.

    Ding, J.; Wang, S.; Wang, Z.; Chen, S.; Zhao, J.; Solomon, M.; Liu, Z.; Guo, F.; Ma, L.; Wen, J.; et al. Schlafen 5 Suppresses Human Immunodeficiency Virus Type 1 Transcription by Commandeering Cellular Epigenetic Machinery. Nucleic Acids Res. 2022, 50, 6137–6153. https://doi.org/10.1093/nar/gkac489.

  • 9.

    Murai, J.; Tang, S.W.; Leo, E.; Baechler, S.A.; Redon, C.E.; Zhang, H.; Al Abo, M.; Rajapakse, V.N.; Nakamura, E.; Jenkins, L.M.M.; et al. SLFN11 Blocks Stressed Replication Forks Independently of ATR. Mol. Cell 2018, 69, 371–384.e6. https://doi.org/10.1016/j.molcel.2018.01.012.

  • 10.

    Huang, J.; Wu, C.; Kloeber, J.A.; Gao, H.; Gao, M.; Zhu, Q.; Chang, Y.; Zhao, F.; Guo, G.; Luo, K.; et al. SLFN5-Mediated Chromatin Dynamics Sculpt Higher-Order DNA Repair Topology. Mol. Cell 2023, 83, 1043–1060.e10. https://doi.org/10.1016/j.molcel.2023.02.004.

  • 11.

    Podvalnaya, N.; Bronkhorst, A.W.; Lichtenberger, R.; Hellmann, S.; Nischwitz, E.; Falk, T.; Karaulanov, E.; Butter, F.; Falk, S.; Ketting, R.F. piRNA Processing by a Trimeric Schlafen-Domain Nuclease. Nature 2023, 622, 402–409. https://doi.org/10.1038/s41586-023-06588-2. Correction in Nature 2024, 632, E31. https://doi.org/10.1038/s41586-024-07938-4.

  • 12.

    Boon, N.J.; Oliveira, R.A.; Körner, P.R.; Kochavi, A.; Mertens, S.; Malka, Y.; Voogd, R.; van der Horst, S.E.M.; Huismans, M.A.; Smabers, L.P.; et al. DNA Damage Induces p53-Independent Apoptosis through Ribosome Stalling. Science 2024, 384, 785–792. https://doi.org/10.1126/science.adh7950.

  • 13.

    Ogawa, A.; Izumikawa, K.; Tate, S.; Isoyama, S.; Mori, M.; Fujiwara, K.; Watanabe, S.; Ohga, T.; Jo, U.; Taniyama, D.; et al. SLFN11-Mediated Ribosome Biogenesis Impairment Induces TP53-Independent Apoptosis. Mol. Cell 2025, 85, 894–912.e10. https://doi.org/10.1016/j.molcel.2025.01.008.

  • 14.

    Ver Donck, F.; Ramaekers, K.; Thys, C.; Van Laer, C.; Peerlinck, K.; Van Geet, C.; Eto, K.; Labarque, V.; Freson, K. Ribosome Dysfunction Underlies SLFN14-Related Thrombocytopenia. Blood 2023, 141, 2261–2274. https://doi.org/10.1182/blood.2022017712.

  • 15.

    Schwarz, D.A.; Katayama, C.D.; Hedrick, S.M. Schlafen, a New Family of Growth Regulatory Genes that Affect Thymocyte Development. Immunity 1998, 9, 657–668. https://doi.org/10.1016/s1074-7613(00)80663-9.

  • 16.

    Geserick, P.; Kaiser, F.; Klemm, U.; Kaufmann, S.H.; Zerrahn, J. Modulation of T Cell Development and Activation by Novel Members of the Schlafen (Slfn) Gene Family Harbouring an RNA Helicase-like Motif. Int. Immunol. 2004, 16, 1535–1548.

  • 17.

    Condamine, T.; Le Luduec, J.B.; Chiffoleau, E.; Beriou, G.; Louvet, C.; Heslan, M.; Tilly, G.; Cuturi, M.C. Characterization of Schlafen-3 Expression in Effector and Regulatory T Cells. J. Leukoc. Biol. 2010, 87, 451–456. https://doi.org/10.1189/jlb.0609410.

  • 18.

    Berger, M.; Krebs, P.; Crozat, K.; Li, X.; Croker, B.A.; Siggs, O.M.; Popkin, D.; Du, X.; Lawson, B.R.; Theofilopoulos, A.N.; et al. An Slfn2 Mutation Causes Lymphoid and Myeloid Immunodeficiency Due to Loss of Immune Cell Quiescence. Nat. Immunol. 2010, 11, 335–343. https://doi.org/10.1038/ni.1847.

  • 19.

    Puck, A.; Aigner, R.; Modak, M.; Cejka, P.; Blaas, D.; Stöckl, J. Expression and Regulation of Schlafen (SLFN) Family Members in Primary Human Monocytes, Monocyte-Derived Dendritic Cells and T Cells. Results Immunol. 2015, 5, 23–32. https://doi.org/10.1016/j.rinim.2015.10.001.

  • 20.

    Vomhof-DeKrey, E.E.; Umthun, J.; Basson, M.D. Loss of Schlafen3 Influences the Expression Levels of Schlafen Family Members in Ileum, Thymus, and Spleen Tissue. PeerJ 2020, 8, e8461. https://doi.org/10.7717/peerj.8461.

  • 21.

    Zhang, P.; Hu, X.; Li, Z.; Liu, Q.; Liu, L.; Jin, Y.; Liu, S.; Zhao, X.; Wang, J.; Hao, D.; et al. Schlafen 11 Triggers Innate Immune Responses through Its Ribonuclease Activity upon Detection of Single-Stranded DNA. Sci. Immunol. 2024, 9, eadj5465. https://doi.org/10.1126/sciimmunol.adj5465.

  • 22.

    Li, M.; Kao, E.; Gao, X.; Sandig, H.; Limmer, K.; Pavon-Eternod, M.; Jones, T.E.; Landry, S.; Pan, T.; Weitzman, M.D.; et al. Codon-Usage-Based Inhibition of HIV Protein Synthesis by Human Schlafen 11. Nature 2012, 491, 125–128. https://doi.org/10.1038/nature11433.

  • 23.

    Yang, J.Y.; Deng, X.Y.; Li, Y.S.; Ma, X.C.; Feng, J.X.; Yu, B.; Chen, Y.; Luo, Y.L.; Wang, X.; Chen, M.L.; et al. Structure of Schlafen13 Reveals a New Class of tRNA/rRNA-Targeting RNase Engaged in Translational Control. Nat. Commun. 2018, 9, 1165. https://doi.org/10.1038/s41467-018-03544-x.

  • 24.

    Valdez, F.; Salvador, J.; Palermo, P.M.; Mohl, J.E.; Hanley, K.A.; Watts, D.; Llano, M. Schlafen 11 Restricts Flavivirus Replication. J. Virol. 2019, 93, e00104-19. https://doi.org/10.1128/jvi.00104-19.

  • 25.

    Kim, E.T.; Weitzman, M.D. Schlafens Can Put Viruses to Sleep. Viruses 2022, 14, 442. https://doi.org/10.3390/v14020442.

  • 26.

    Seong, R.K.; Seo, S.W.; Kim, J.A.; Fletcher, S.J.; Morgan, N.V.; Kumar, M.; Choi, Y.K.; Shin, O.S. Schlafen 14 (SLFN14) Is a Novel Antiviral Factor Involved in the Control of Viral Replication. Immunobiology 2017, 222, 979–988. https://doi.org/10.1016/j.imbio.2017.07.002.

  • 27.

    Jitobaom, K.; Sirihongthong, T.; Boonarkart, C.; Phakaratsakul, S.; Suptawiwat, O.; Auewarakul, P. Human Schlafen 11 Inhibits Influenza a Virus Production. Virus Res. 2023, 334, 199162. https://doi.org/10.1016/j.virusres.2023.199162.

  • 28.

    Kobayashi-Ishihara, M.; Frazão Smutná, K.; Alonso, F.E.; Argilaguet, J.; Esteve-Codina, A.; Geiger, K.; Genescà, M.; Grau-Expósito, J.; Duran-Castells, C.; Rogenmoser, S. Schlafen 12 Restricts HIV-1 Latency Reversal by a Codon-Usage Dependent Post-Transcriptional Block in CD4+ T Cells. Commun. Biol. 2023, 6, 487.

  • 29.

    Valenzuela, C.; Saucedo, S.; Llano, M. Schlafen14 Impairs HIV-1 Expression in a Codon Usage-Dependent Manner. Viruses 2024, 16, 502. https://doi.org/10.3390/v16040502.

  • 30.

    Katsoulidis, E.; Mavrommatis, E.; Woodard, J.; Shields, M.A.; Sassano, A.; Carayol, N.; Sawicki, K.T.; Munshi, H.G.; Platanias, L.C. Role of Interferon α (IFNα)-Inducible Schlafen-5 in Regulation of Anchorage-Independent Growth and Invasion of Malignant Melanoma Cells. J. Biol. Chem. 2010, 285, 40333–40341. https://doi.org/10.1074/jbc.m110.151076.

  • 31.

    Sassano, A.; Mavrommatis, E.; Arslan, A.D.; Kroczynska, B.; Beauchamp, E.M.; Khuon, S.; Chew, T.L.; Green, K.J.; Munshi, H.G.; Verma, A.K.; et al. Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells. Mol. Cell. Biol. 2015, 35, 2684–2698. https://doi.org/10.1128/mcb.00019-15.

  • 32.

    Zhou, C.; Liu, C.; Liu, W.; Chen, W.; Yin, Y.; Li, C.W.; Hsu, J.L.; Sun, J.; Zhou, Q.; Li, H.; et al. SLFN11 Inhibits Hepatocellular Carcinoma Tumorigenesis and Metastasis by Targeting RPS4X via mTOR Pathway. Theranostics 2020, 10, 4627–4643. https://doi.org/10.7150/thno.42869.

  • 33.

    Chen, J.; Liu, N.; Huang, Y.; Wang, Y.; Sun, Y.; Wu, Q.; Li, D.; Gao, S.; Wang, H.W.; Huang, N.; et al. Structure of PDE3A-SLFN12 Complex and Structure-Based Design for a Potent Apoptosis Inducer of Tumor Cells. Nat. Commun. 2021, 12, 6204. https://doi.org/10.1038/s41467-021-26546-8.

  • 34.

    Wan, G.; Zhu, J.; Gu, X.; Yang, Y.; Liu, Y.; Wang, Z.; Zhao, Y.; Wu, H.; Huang, G.; Lu, C. Human Schlafen 5 Regulates Reversible Epithelial and Mesenchymal Transitions in Breast Cancer by Suppression of ZEB1 Transcription. Br. J. Cancer 2020, 123, 633–643. https://doi.org/10.1038/s41416-020-0873-z.

  • 35.

    Fischietti, M.; Eckerdt, F.; Blyth, G.T.; Arslan, A.D.; Mati, W.M.; Oku, C.V.; Perez, R.E.; Lee-Chang, C.; Kosciuczuk, E.M.; Saleiro, D.; et al. Schlafen 5 as a Novel Therapeutic Target in Pancreatic Ductal Adenocarcinoma. Oncogene 2021, 40, 3273–3286. https://doi.org/10.1038/s41388-021-01761-1.

  • 36.

    Zhou, C.; Weng, J.; Liu, C.; Liu, S.; Hu, Z.; Xie, X.; Gao, D.; Zhou, Q.; Sun, J.; Xu, R. Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma. Gastroenterology 2023, 164, 1261–1278. https://doi.org/10.1053/j.gastro.2023.02.005.

  • 37.

    Akashi, H.; Yachida, N.; Ueda, H.; Yamaguchi, M.; Yamawaki, K.; Tamura, R.; Suda, K.; Ishiguro, T.; Adachi, S.; Nagase, Y.; et al. SLFN11 Is a BRCA-Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma. Mol. Cancer Ther. 2024, 23, 106–116. https://doi.org/10.1158/1535-7163.mct-23-0257.

  • 38.

    Li, J.; Chen, Z.; Jin, M.; Gu, X.; Wang, Y.; Huang, G.; Zhao, W.; Lu, C. Histone H4K12 Lactylation Promotes Malignancy Progression in Triple-Negative Breast Cancer through SLFN5 Downregulation. Cell. Signal. 2024, 124, 111468. https://doi.org/10.1016/j.cellsig.2024.111468.

  • 39.

    Wu, Y.J.; Chiao, C.C.; Chuang, P.K.; Hsieh, C.B.; Ko, C.Y.; Ko, C.C.; Chang, C.F.; Chen, T.Y.; Nguyen, N.U.N.; Hsu, C.C.; et al. Comprehensive Analysis of Bulk and Single-Cell RNA Sequencing Data Reveals Schlafen-5 (SLFN5) as a Novel Prognosis and Immunity Biomarker. Int. J. Med. Sci. 2024, 21, 2348–2364. https://doi.org/10.7150/ijms.97975.

  • 40.

    Neumann, B.; Zhao, L.; Murphy, K.; Gonda, T.J. Subcellular Localization of the Schlafen Protein Family. Biochem. Biophys. Res. Commun. 2008, 370, 62–66. https://doi.org/10.1016/j.bbrc.2008.03.032.

  • 41.

    Jo, U.; Pommier, Y. Structural, Molecular, and Functional Insights into Schlafen Proteins. Exp. Mol. Med. 2022, 54, 730–738. https://doi.org/10.1038/s12276-022-00794-0.

  • 42.

    Bustos, O.; Naik, S.; Ayers, G.; Casola, C.; Perez-Lamigueiro, M.A.; Chippindale, P.T.; Pritham, E.J.; de la Casa-Esperón, E. Evolution of the Schlafen Genes, a Gene Family Associated with Embryonic Lethality, Meiotic Drive, Immune Processes and Orthopoxvirus Virulence. Gene 2009, 447, 1–11. https://doi.org/10.1016/j.gene.2009.07.006.

  • 43.

    Metzner, F.J.; Wenzl, S.J.; Kugler, M.; Krebs, S.; Hopfner, K.P.; Lammens, K. Mechanistic Understanding of Human SLFN11. Nat. Commun. 2022, 13, 5464. https://doi.org/10.1038/s41467-022-33123-0.

  • 44.

    Luo, M.; Jia, X.; Wang, Z.W.; Yang, J.Y.; Wang, W.; Chen, J.; Ou, J.Y.; Feng, J.X.; Yu, B.; Wang, S.; et al. Structural and Functional Characterization of Human SLFN14. Nucleic Acids Res. 2025, 53, gkaf484. https://doi.org/10.1093/nar/gkaf484.

  • 45.

    Wan, G.; Liu, Y.; Zhu, J.; Guo, L.; Li, C.; Yang, Y.; Gu, X.; Deng, L.L.; Lu, C. SLFN5 Suppresses Cancer Cell Migration and Invasion by Inhibiting MT1-MMP Expression via AKT/GSK-3β/β-Catenin Pathway. Cell. Signal. 2019, 59, 1–12. https://doi.org/10.1016/j.cellsig.2019.03.004.

  • 46.

    Ding, J.; Wang, S.; Liu, Q.; Duan, Y.; Cheng, T.; Ye, Z.; Cui, Z.; Zhang, A.; Liu, Q.; Zhang, Z.; et al. Schlafen-5 Inhibits LINE-1 Retrotransposition. iScience 2023, 26, 107968. https://doi.org/10.1016/j.isci.2023.107968.

  • 47.

    Vonrhein, C.; Flensburg, C.; Keller, P.; Sharff, A.; Smart, O.; Paciorek, W.; Womack, T.; Bricogne, G. Data Processing and Analysis with the AutoPROC Toolbox. Acta Crystallogr. D Biol. Crystallogr. 2011, 67, 293–302. https://doi.org/10.1107/s0907444911007773.

  • 48.

    Collaborative Computational Project, Number 4. The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallogr. Sect. D Biol. Crystallogr. 1994, 50, 760–763. https://doi.org/10.1107/s0907444994003112.

  • 49.

    Emsley, P.; Cowtan, K. Coot: Model-Building Tools for Molecular Graphics. Acta Crystallogr. Sect. D Biol. Crystallogr. 2004, 60, 2126–2132. https://doi.org/10.1107/s0907444904019158.

  • 50.

    Winn, M.D.; Murshudov, G.N.; Papiz, M.Z. Macromolecular TLS Refinement in REFMAC at Moderate Resolutions. Methods Enzymol. 2003, 374, 300–321. https://doi.org/10.1016/s0076-6879(03)74014-2.

  • 51.

    Adams, P.D.; Afonine, P.V.; Bunkóczi, G.; Chen, V.B.; Davis, I.W.; Echols, N.; Headd, J.J.; Hung, L.W.; Kapral, G.J.; Grosse-Kunstleve, R.W.; et al. PHENIX: A Comprehensive Python-Based System for Macromolecular Structure Solution. Acta Crystallogr. D Biol. Crystallogr. 2010, 66, 213–221. https://doi.org/10.1107/s0907444909052925.

  • 52.

    Joosten, R.P.; Long, F.; Murshudov, G.N.; Perrakis, A. The PDB_REDO Server for Macromolecular Structure Model Optimization. IUCrJ 2014, 1, 213–220. https://doi.org/10.1107/s2052252514009324.

  • 53.

    Chen, V.B.; Arendall, W.B., III; Headd, J.J.; Keedy, D.A.; Immormino, R.M.; Kapral, G.J.; Murray, L.W.; Richardson, J.S.; Richardson, D.C. MolProbity: All-Atom Structure Validation for Macromolecular Crystallography. Acta Crystallogr. D Biol. Crystallogr. 2010, 66, 12–21. https://doi.org/10.1107/s0907444909042073.

  • 54.

    Cancer Genome Atlas Network. Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. Nature 2012, 487, 330–337. https://doi.org/10.1038/nature11252.

  • 55.

    Guichard, C.; Amaddeo, G.; Imbeaud, S.; Ladeiro, Y.; Pelletier, L.; Maad, I.B.; Calderaro, J.; Bioulac-Sage, P.; Letexier, M.; Degos, F.; et al. Integrated Analysis of Somatic Mutations and Focal Copy-Number Changes Identifies Key Genes and Pathways in Hepatocellular Carcinoma. Nat. Genet. 2012, 44, 694–698. https://doi.org/10.1038/ng.2256.

  • 56.

    Imielinski, M.; Berger, A.H.; Hammerman, P.S.; Hernandez, B.; Pugh, T.J.; Hodis, E.; Cho, J.; Suh, J.; Capelletti, M.; Sivachenko, A.; et al. Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing. Cell 2012, 150, 1107–1120. https://doi.org/10.1016/j.cell.2012.08.029.

  • 57.

    Omar, I.; Guterman-Ram, G.; Rahat, D.; Tabach, Y.; Berger, M.; Levaot, N. Schlafen2 Mutation in Mice Causes an Osteopetrotic Phenotype Due to a Decrease in the Number of Osteoclast Progenitors. Sci. Rep. 2018, 8, 13005.

  • 58.

    García del Arco, A.; Erhardt, S. Post-Translational Modifications of Centromeric Chromatin. Prog. Mol. Subcell. Biol. 2017, 56, 213–231. https://doi.org/10.1007/978-3-319-58592-5_9.

  • 59.

    Mavrommatis, E.; Arslan, A.D.; Sassano, A.; Hua, Y.; Kroczynska, B.; Platanias, L.C. Expression and Regulatory Effects of Murine Schlafen (Slfn) Genes in Malignant Melanoma and Renal Cell Carcinoma. J. Biol. Chem. 2013, 288, 33006–33015. https://doi.org/10.1074/jbc.m113.460741.

  • 60.

    Li, M.; Kao, E.; Malone, D.; Gao, X.; Wang, J.Y.J.; David, M. DNA Damage-Induced Cell Death Relies on SLFN11-Dependent Cleavage of Distinct Type II tRNAs. Nat. Struct. Mol. Biol. 2018, 25, 1047–1058. https://doi.org/10.1038/s41594-018-0142-5.

  • 61.

    Garvie, C.W.; Wu, X.; Papanastasiou, M.; Lee, S.; Fuller, J.; Schnitzler, G.R.; Horner, S.W.; Baker, A.; Zhang, T.; Mullahoo, J.P.; et al. Structure of PDE3A-SLFN12 Complex Reveals Requirements for Activation of SLFN12 RNase. Nat. Commun. 2021, 12, 4375. https://doi.org/10.1038/s41467-021-24495-w.

  • 62.

    Pisareva, V.P.; Muslimov, I.A.; Tcherepanov, A.; Pisarev, A.V. Characterization of Novel Ribosome-Associated Endoribonuclease SLFN14 from Rabbit Reticulocytes. Biochemistry 2015, 54, 3286–3301. https://doi.org/10.1021/acs.biochem.5b00302.

  • 63.

    Lipfert, J.; Skinner, G.M.; Keegstra, J.M.; Hensgens, T.; Jager, T.; Dulin, D.; Kober, M.; Yu, Z.; Donkers, S.P.; Chou, F.C.; et al. Double-Stranded RNA under Force and Torque: Similarities to and Striking Differences from Double-Stranded DNA. Proc. Natl. Acad. Sci. USA 2014, 111, 15408–15413. https://doi.org/10.1073/pnas.1407197111.

  • 64.

    Callaghan, A.J.; Aurikko, J.P.; Ilag, L.L.; Grossmann, J.G.; Chandran, V.; Kühnel, K.; Poljak, L.; Carpousis, A.J.; Robinson, C.V.; Symmons, M.F.; et al. Studies of the RNA Degradosome-Organizing Domain of the Escherichia coli Ribonuclease RNase E. J. Mol. Biol. 2004, 340, 965–979. https://doi.org/10.1016/j.jmb.2004.05.046.

  • 65.

    Gan, J.; Tropea, J.E.; Austin, B.P.; Court, D.L.; Waugh, D.S.; Ji, X. Structural Insight into the Mechanism of Double-Stranded RNA Processing by Ribonuclease III. Cell 2006, 124, 355–366. https://doi.org/10.1016/j.cell.2005.11.034.

  • 66.

    Murchison, E.P.; Hannon, G.J. miRNAs on the Move: miRNA Biogenesis and the RNAi Machinery. Curr. Opin. Cell Biol. 2004, 16, 223–229. https://doi.org/10.1016/j.ceb.2004.04.003.

  • 67.

    Söderbom, F.; Svärd, S.G.; Kirsebom, L.A. RNase E Cleavage in the 5′ Leader of a tRNA Precursor. J. Mol. Biol. 2005, 352, 22–27. https://doi.org/10.1016/j.jmb.2005.07.003.

  • 68.

    Hirata, A.; Kitajima, T.; Hori, H. Cleavage of Intron from the Standard or Non-Standard Position of the Precursor tRNA by the Splicing Endonuclease of Aeropyrum pernix, a Hyper-Thermophilic Crenarchaeon, Involves a Novel RNA Recognition Site in the Crenarchaea Specific Loop. Nucleic Acids Res. 2011, 39, 9376–9389. https://doi.org/10.1093/nar/gkr615.

  • 69.

    Jiao, Y.; Yonescu, R.; Offerhaus, G.J.A.; Klimstra, D.S.; Maitra, A.; Eshleman, J.R.; Herman, J.G.; Poh, W.; Pelosof, L.; Wolfgang, C.L.; et al. Whole-Exome Sequencing of Pancreatic Neoplasms with Acinar Differentiation. J. Pathol. 2014, 232, 428–435. https://doi.org/10.1002/path.4310.

  • 70.

    Czuba, L.C.; Hillgren, K.M.; Swaan, P.W. Post-Translational Modifications of Transporters. Pharmacol. Ther. 2018, 192, 88–99. https://doi.org/10.1016/j.pharmthera.2018.06.013.

  • 71.

    Thompson, J.D.; Higgins, D.G.; Gibson, T.J. CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment through Sequence Weighting, Position-Specific Gap Penalties and Weight Matrix Choice. Nucleic Acids Res. 1994, 22, 4673–4680.

Share this article:
Download PDF
Supplementary Materials
DOI
10.53941/hm.2026.100021
Issue
Volume 3, Issue 3
How to Cite
Yang, J.-Y.; Ou, J.-Y.; Luo, M.; Wang, Z.-W.; Zheng, Y.-Q.; Liu, Z.-X.; Gao, S. Structural and Biochemical Analysis of Human Schlafen5 Reveals the Molecular Basis of Its Anti-Tumor Function. Health and Metabolism 2026, 3 (3), 7. https://doi.org/10.53941/hm.2026.100021.
RIS
BibTex
Copyright & License
article copyright Image
Copyright (c) 2026 by the authors.