Mechanistic Understanding of Human SLFN11

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Sep 17

PMID 36115853

Authors

Felix J Metzner

Simon J Wenzl

Michael Kugler

Stefan Krebs

Karl-Peter Hopfner

Katja Lammens

Affiliations

Soon will be listed here.

Abstract

Schlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.

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References

Bepler T, Morin A, Rapp M, Brasch J, Shapiro L, Noble A . Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs. Nat Methods. 2019; 16(11):1153-1160. PMC: 6858545. DOI: 10.1038/s41592-019-0575-8. View

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

Garvie C, Wu X, Papanastasiou M, Lee S, Fuller J, Schnitzler G . Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase. Nat Commun. 2021; 12(1):4375. PMC: 8285493. DOI: 10.1038/s41467-021-24495-w. View

Zoppoli G, Regairaz M, Leo E, Reinhold W, Varma S, Ballestrero A . Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc Natl Acad Sci U S A. 2012; 109(37):15030-5. PMC: 3443151. DOI: 10.1073/pnas.1205943109. View

Afonine P, Grosse-Kunstleve R, Echols N, Headd J, Moriarty N, Mustyakimov M . Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):352-67. PMC: 3322595. DOI: 10.1107/S0907444912001308. View

Zheng S, Palovcak E, Armache J, Verba K, Cheng Y, Agard D . MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat Methods. 2017; 14(4):331-332. PMC: 5494038. DOI: 10.1038/nmeth.4193. View

Coussy F, El-Botty R, Chateau-Joubert S, Dahmani A, Montaudon E, Leboucher S . BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med. 2020; 12(531). PMC: 8662740. DOI: 10.1126/scitranslmed.aax2625. View

Fairman-Williams M, Guenther U, Jankowsky E . SF1 and SF2 helicases: family matters. Curr Opin Struct Biol. 2010; 20(3):313-24. PMC: 2916977. DOI: 10.1016/j.sbi.2010.03.011. View

Popenda M, Szachniuk M, Antczak M, Purzycka K, Lukasiak P, Bartol N . Automated 3D structure composition for large RNAs. Nucleic Acids Res. 2012; 40(14):e112. PMC: 3413140. DOI: 10.1093/nar/gks339. View

10.

Valdez F, Salvador J, Palermo P, Mohl J, Hanley K, Watts D . Schlafen 11 Restricts Flavivirus Replication. J Virol. 2019; 93(15). PMC: 6639263. DOI: 10.1128/JVI.00104-19. View

11.

Punjani A, Rubinstein J, Fleet D, Brubaker M . cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3):290-296. DOI: 10.1038/nmeth.4169. View

12.

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

13.

Metzner F, Huber E, Hopfner K, Lammens K . Structural and biochemical characterization of human Schlafen 5. Nucleic Acids Res. 2022; 50(2):1147-1161. PMC: 8789055. DOI: 10.1093/nar/gkab1278. View

14.

Perkins D, Pappin D, Creasy D, Cottrell J . Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis. 1999; 20(18):3551-67. DOI: 10.1002/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2. View

15.

Lok B, Gardner E, Schneeberger V, Ni A, Desmeules P, Rekhtman N . PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer. Clin Cancer Res. 2016; 23(2):523-535. PMC: 5241177. DOI: 10.1158/1078-0432.CCR-16-1040. View

16.

Li M, Kao E, Malone D, Gao X, Wang J, David M . DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs. Nat Struct Mol Biol. 2018; 25(11):1047-1058. PMC: 6579113. DOI: 10.1038/s41594-018-0142-5. View

17.

Murai J, Zhang H, Pongor L, Tang S, Jo U, Moribe F . Chromatin Remodeling and Immediate Early Gene Activation by SLFN11 in Response to Replication Stress. Cell Rep. 2020; 30(12):4137-4151.e6. PMC: 7240837. DOI: 10.1016/j.celrep.2020.02.117. View

18.

Murai J, Feng Y, Yu G, Ru Y, Tang S, Shen Y . Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget. 2016; 7(47):76534-76550. PMC: 5340226. DOI: 10.18632/oncotarget.12266. View

19.

Nightingale K, Potts M, Hunter L, Fielding C, Zerbe C, Fletcher-Etherington A . Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 2022; 119(6). PMC: 8832970. DOI: 10.1073/pnas.2108173119. View

20.

Malone D, Lardelli R, Li M, David M . Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response. J Biol Chem. 2019; 294(40):14674-14685. PMC: 6779438. DOI: 10.1074/jbc.RA118.006588. View