Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Recruitment and activation of the ATM kinase in the absence of DNA-damage sensors

Nature Structural & Molecular Biology volume 22, pages 736–743 (2015)Cite this article

Subjects

Abstract

Two kinases, ATM and DNA-PKcs, control rapid responses to DNA double-strand breaks (DSBs). The paradigm for ATM control is recruitment and activation by the Mre11−Rad50−NBS1 (MRN) sensor complex, whereas DNA-PKcs requires the sensor Ku (Ku70−Ku80). Using mouse cells containing targeted mutant alleles of Mre11 (Mre11a) and/or Ku70 (Xrcc6), together with pharmacologic kinase inhibition, we demonstrate that ATM can be activated by DSBs in the absence of MRN. When MRN is deficient, DNA-PKcs efficiently substitutes for ATM in facilitating local chromatin responses. In the absence of both MRN and Ku, ATM is recruited to chromatin, where it phosphorylates H2AX and triggers the G2-M cell-cycle checkpoint, but the DNA-repair functions of MRN are not restored. These results suggest that, in contrast to straightforward recruitment and activation by MRN, a complex interplay between sensors has a substantial role in ATM control.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The early response to DNA DSBs.
Figure 2: MRN and Ku relocate to DSBs independently in the early DSB response.
Figure 3: Ku loss bypasses the need for MRN in activating the G2-M checkpoint.
Figure 4: Ku loss does not bypass the need for MRN in DSB repair.
Figure 5: ATM recruitment and activation in the absence of DSB sensors.
Figure 6: MDC1 recruitment in the absence of MRN and Ku.
Figure 7: Comparisons of ATM activation in the presence versus absence of DSB sensors.

Similar content being viewed by others

References

  1. Jackson, S.P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Symington, L.S. & Gautier, J. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45, 247–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Ciccia, A. & Elledge, S.J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goodarzi, A.A. & Jeggo, P.A. The repair and signaling responses to DNA double-strand breaks. Adv. Genet. 82, 1–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Falck, J., Coates, J. & Jackson, S.P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. McKinnon, P.J. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu. Rev. Pathol. 7, 303–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Uziel, T. et al. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 22, 5612–5621 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee, J.H. & Paull, T.T. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26, 7741–7748 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14, 197–210 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Price, B.D. & D'Andrea, A.D. Chromatin remodeling at DNA double-strand breaks. Cell 152, 1344–1354 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, J.H. & Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Stracker, T.H., Roig, I., Knobel, P.A. & Marjanovic, M. The ATM signaling network in development and disease. Front. Genet. 4, 37 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Buis, J. et al. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135, 85–96 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dupré, A., Boyer-Chatenet, L. & Gautier, J. Two-step activation of ATM by DNA and the Mre11–Rad50–Nbs1 complex. Nat. Struct. Mol. Biol. 13, 451–457 (2006).

    Article  PubMed  CAS  Google Scholar 

  16. Dynan, W.S. & Yoo, S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res. 26, 1551–1559 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Walker, J.R., Corpina, R.A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Davis, A.J., Chen, B.P. & Chen, D.J. DNA-PK: a dynamic enzyme in a versatile DSB repair pathway. DNA Repair (Amst.) 17, 21–29 (2014).

    Article  CAS  Google Scholar 

  19. Gao, Y. et al. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9, 367–376 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Jhappan, C., Morse, H.C. III., Fleischmann, R.D., Gottesman, M.M. & Merlino, G. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat. Genet. 17, 483–486 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Carson, C.T. et al. The Mre11 complex is required for ATM activation and the G2/M checkpoint. EMBO J. 22, 6610–6620 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Bressan, D.A., Baxter, B.K. & Petrini, J.H. The Mre11-Rad50-Xrs2 protein complex facilitates homologous recombination-based double-strand break repair in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 7681–7687 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tomita, K. et al. Competition between the Rad50 complex and the Ku heterodimer reveals a role for Exo1 in processing double-strand breaks but not telomeres. Mol. Cell. Biol. 23, 5186–5197 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pierce, A.J., Johnson, R.D., Thompson, L.H. & Jasin, M. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 13, 2633–2638 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Helleday, T. Pathways for mitotic homologous recombination in mammalian cells. Mutat. Res. 532, 103–115 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Andegeko, Y. et al. Nuclear retention of ATM at sites of DNA double strand breaks. J. Biol. Chem. 276, 38224–38230 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Rogakou, E.P., Boon, C., Redon, C. & Bonner, W.M. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J. Cell Biol. 146, 905–916 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu, X. & Stern, D.F. NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. J. Biol. Chem. 278, 8795–8803 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213–1226 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Lou, Z. et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 21, 187–200 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Fernandez-Capetillo, O. et al. DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1. Nat. Cell Biol. 4, 993–997 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Lan, L. et al. Accumulation of Werner protein at DNA double-strand breaks in human cells. J. Cell Sci. 118, 4153–4162 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Shibata, A. et al. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol. Cell 53, 7–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Williams, R.S. et al. Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135, 97–109 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zou, L. & Elledge, S.J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Stiff, T. et al. ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J. 25, 5775–5782 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Prevo, R. et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol. Ther. 13, 1072–1081 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bakkenist, C.J. & Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Pellegrini, M. et al. Autophosphorylation at serine 1987 is dispensable for murine Atm activation in vivo. Nature 443, 222–225 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Sun, J., Lee, K.J., Davis, A.J. & Chen, D.J. Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J. Biol. Chem. 287, 4936–4945 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Langerak, P., Mejia-Ramirez, E., Limbo, O. & Russell, P. Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 is required for homologous recombination repair of double-strand breaks. PLoS Genet. 7, e1002271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shao, Z. et al. Persistently bound Ku at DNA ends attenuates DNA end resection and homologous recombination. DNA Repair (Amst.) 11, 310–316 (2012).

    Article  CAS  PubMed Central  Google Scholar 

  45. Blier, P.R., Griffith, A.J., Craft, J. & Hardin, J.A. Binding of Ku protein to DNA: measurement of affinity for ends and demonstration of binding to nicks. J. Biol. Chem. 268, 7594–7601 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Paull, T.T. & Deshpande, R.A. The Mre11/Rad50/Nbs1 complex: recent insights into catalytic activities and ATP-driven conformational changes. Exp. Cell Res. 329, 139–147 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Deshpande, R.A. et al. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO J. 33, 482–500 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Difilippantonio, S. et al. Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis. J. Exp. Med. 204, 1003–1011 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stracker, T.H., Morales, M., Couto, S.S., Hussein, H. & Petrini, J.H. The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex. Nature 447, 218–221 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith, G.C. et al. Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM. Proc. Natl. Acad. Sci. USA 96, 11134–11139 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Nakada, S. et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466, 941–946 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Nutley, B.P. et al. Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br. J. Cancer 93, 1011–1018 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zha, S. et al. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc. Natl. Acad. Sci. USA 108, 2028–2033 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Regal, J.A., Festerling, T.A., Buis, J.M. & Ferguson, D.O. Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. Hum. Mol. Genet. 22, 5146–5159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang, R.H. et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312–323 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Taniguchi, T. et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109, 459–472 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Li, M. & Yu, X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23, 693–704 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Van Hooser, A., Goodrich, D.W., Allis, C.D., Brinkley, B.R. & Mancini, M.A. Histone H3 phosphorylation is required for the initiation, but not maintenance, of mammalian chromosome condensation. J. Cell Sci. 111, 3497–3506 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Theunissen, J.W. & Petrini, J.H. Methods for studying the cellular response to DNA damage: influence of the Mre11 complex on chromosome metabolism. Methods Enzymol. 409, 251–284 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank X. Yu (University of Michigan) for reagents and for use of the laser microirradiation apparatus, M. Jasin (Memorial Sloan Kettering Cancer Center) for the DR-GFP reporter, F. Graham and P. Ng (McMaster University) for the AdNGUS24i I-SceI adenovirus and J. Sekiguchi for helpful discussions regarding the manuscript. Support for this work was provided by US National Institutes of Health (NIH) grant R01-HL079118 (D.O.F.), a Leukemia and Lymphoma Society Scholar Grant (D.O.F.) and University of Michigan Cancer Center Support Grant 5-P30-CA46592. A.J.H. was supported by NIH grant T32 CA009676 and M.J.M. by NIH grant T32 AI007413.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Andrea J Hartlerode, Mary J Morgan, Yipin Wu, Jeffrey Buis & David O Ferguson

Authors
  1. Andrea J Hartlerode
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary J Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yipin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey Buis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David O Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.J.H. planned and performed most experiments, analyzed and interpreted the data and participated in writing all portions of the manuscript. Y.W. performed and interpreted experiments in Figure 7d,e and Supplementary Figures 6 and 7e. M.J.M. performed and interpreted immunofluorescent foci experiments in Figure 5c and Supplementary Figures 3c,d and 4, and assisted A.J.H. with the laser microirradiation experiments in Figures 2a and 6. J.B. performed initial mouse breeding and analyses of Mendelian inheritance (Supplementary Table 1). D.O.F. participated in the design of all experiments as well as analyses and interpretation of data, and in writing of the manuscript.

Corresponding author

Correspondence to David O Ferguson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Confirmation of Mre11 and Ku70 knockouts.

Immunoblots of Mre11 and Ku70 levels 30 minutes after IR (10 Gy). Genotypes are as shown. This confirms the genotypes shown and demonstrates that the levels of these proteins are not impacted by exposure to IR.

Supplementary Figure 2 Ku recruitment is unaltered in MRN-deficient cells.

(a,b) Quantitation of Ku fluorescence intensity at the site of laser microirradiation (example images shown in Figure 2b). Data shown are means and s.e.m. (n = 88 cells over 3 cell-culture replicates). p-values were calculated using an unpaired t-test.

Supplementary Figure 3 ATM target phosphorylations and ATM-dependent 53BP1 foci formation in the absence of MRN and Ku.

(a) Immunoblot of various protein levels 30 minutes after IR (10 Gy), with or without pretreatment with kinase inhibitors (ATMi, ATM inhibitor; PKi, DNA-PK inhibitor; AiPKi, ATM and DNA-PK inhibitors). Note that ATM-dependent phosphorylations are restored by Mre11 and Ku deficiency, but less efficiently than controls. (b) Quantification of pKap1S824 levels normalized to total Kap1 levels from immunoblots. Data shown are mean and s.e.m. (n = 3 cell-culture replicates). Results indicate a 60 to 70% reduction in pKap1S824 levels in the absence of MRN and Ku compared to controls. (c) 53BP1 immunofluorescent foci (green) 30 min after IR (3Gy), with or without pretreatment with kinase inhibitors (ATMi, PKi, and AiPKi). Nuclei are stained with 4’,6-diamidino-2-phenylindole (DAPI; blue). Genotypes are as shown. Scale bars, 10 μm. (d) Quantification of 53BP1 foci. Data shown are means and s.e.m. (n = 3 cell-culture replicates). Note that only a portion of 53BP1 foci formation is dependent on DNA damage kinases.

Supplementary Figure 4 γH2AX foci are unaltered in MRN- and Ku-deficient cells.

Graph shows the quantification of γH2AX immunofluorescent foci (representative images shown in Fig. 5c) 30 min after IR, with or without pretreatment with kinase inhibitors (ATMi, ATM inhibitor; PKi, DNA-PK inhibitor; AiPKi, ATM and DNA-PK inhibitors). Genotypes are as shown. Data shown are means and s.e.m. (n = 3 cell-culture replicates). The majority of cells (65 to 80%) contained 10 or more γH2AX foci and the morphology of these foci (Fig. 5c) were similar amongst all genotypes.

Supplementary Figure 5 Sensor-independent ATM activation in diverse experimental conditions.

(a) Immunoblot of γH2AX levels 30 min after IR at doses ranging from 0.5 to 5 Gy. Genotypes are as shown. (b,c) Immunoblot as in (a) 30 min after IR at doses as indicated, with or without pretreatment with kinase inhibitors (ATMi, ATM inhibitor; PKi, DNA-PK inhibitor; AiPKi, ATM and DNA-PK inhibitors). Genotypes are as shown. Note that the pattern of kinase dependence does not change at lower or higher doses of IR in any genotype. (d) Immunoblot of γH2AX levels at various time points after IR. Genotypes are as shown. (e) Immunoblot of protein levels in cellular fractions (top) prepared 30 min after IR or with no IR. Genotypes are as shown. This demonstrates that ATM recruited to chromatin in MRN- and Ku-deficient cells is not phosphorylated on S1987.

Supplementary Figure 6 DNA-PKcs can fully substitute for ATM only when MRN is absent.

γH2AX immunofluorescent foci (green) 30 min after IR (3 Gy), with or without DNA-PK kinase inhibitor (PKi) pretreatment. Genotypes are as shown. Scale bars, 40 μm. In line with immunoblot data, DNA-PK inhibition has little impact on γH2AX focus formation in control (Mre11+/–) and Mre11 nuclease-deficient cells (Mre11H129N/–). γH2AX foci are noticeably dimmer in ATM-deficient cells compared to Mre11-deficient cells, demonstrating that loss of MRN (not loss of ATM activity), permits activation DNA-PKcs.

Supplementary Figure 7 Representative duplicates of key experiments.

(a) Immunoblot of various protein levels 30 minutes after IR, with or without pretreatment with kinase inhibitors (ATMi, ATM inhibitor; PKi, DNA-PK inhibitor; AiPKi, ATM and DNA-PK inhibitors). Genotypes are as shown. (b) Immunoblot of protein levels in cellular fractions (top) prepared 30 min after IR or with no IR. Genotypes are as shown. (c,d) Immunoblot of various protein levels as in (a). (e) Immunoblots of γH2AX levels at various time points after IR, with or without pretreatment with the DNA-PK inhibitor (PKi). Genotypes are as shown.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Table 1 (PDF 1085 kb)

Supplementary Data Set 1

Uncropped images of immunoblots from key experiments (PDF 13602 kb)

Comparison of Ku recruitment in control versus MRN-deficient cells

GFP-tagged Ku70 and Ku80 were expressed in cells of the indicated genotypes and relocation kinetics were measured continuously via fluorescent microscopy video capture. The laser pulse is identified by a dark spot due to photo-bleaching of diffuse nuclear GFP-Ku. Time zero is defined as the first frame with an identifiable laser induced photo-bleached spot. Movies are shown side by side in real-time followed by one-tenth speed to allow closer comparison of protein recruitment. Initial video capture was at 3 frames per second. Movies were composited and labeled using Final Cut Pro X (Apple Inc.). (MOV 4534 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hartlerode, A., Morgan, M., Wu, Y. et al. Recruitment and activation of the ATM kinase in the absence of DNA-damage sensors. Nat Struct Mol Biol 22, 736–743 (2015). https://doi.org/10.1038/nsmb.3072

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3072

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing