Skip to main content
Log in

Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria

Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen. Interestingly, a significant increase in the efficiency of HR was observed when a DSB was introduced. Analyses of the clones suggest that most of the recombinants were generated through reciprocal exchange, while ~ 30% of recombinants were due to gene conversion in testicular extracts. Colocalization and immunoblotting studies showed the presence of RAD51 and MRN complex proteins in the mitochondria and immunodepletion of MRE11, RAD51 or NIBRIN suppressed the HR-mediated repair. Thus, our results reveal importance of homologous recombination in the maintenance of mitochondrial genome stability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Drablos F, Feyzi E, Aas PA, Vaagbo CB, Kavli B, Bratlie MS, Pena-Diaz J, Otterlei M, Slupphaug G, Krokan HE (2004) Alkylation damage in DNA and RNA—repair mechanisms and medical significance. DNA Repair (Amst) 3:1389–1407. https://doi.org/10.1016/j.dnarep.2004.05.004

    Article  CAS  Google Scholar 

  2. Gostissa M, Alt FW, Chiarle R (2011) Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu Rev Immunol 29:319–350. https://doi.org/10.1146/annurev-immunol-031210-101329

    Article  CAS  PubMed  Google Scholar 

  3. Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214. https://doi.org/10.1096/fj.02-0752rev

    Article  CAS  PubMed  Google Scholar 

  4. Barnes DE, Lindahl T (2004) Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 38:445–476. https://doi.org/10.1146/annurev.genet.38.072902.092448

    Article  CAS  PubMed  Google Scholar 

  5. Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015) Homology and enzymatic requirements of microhomology-dependent alternative end joining. Cell Death Dis 6:e1697. https://doi.org/10.1038/cddis.2015.58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Javadekar SM, Raghavan SC (2015) Snaps and mends: DNA breaks and chromosomal translocations. FEBS J 282:2627–2645. https://doi.org/10.1111/febs.13311

    Article  CAS  PubMed  Google Scholar 

  7. Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078. https://doi.org/10.1038/nature08467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nambiar M, Raghavan SC (2011) How does DNA break during chromosomal translocations? Nucleic Acids Res 39:5813–5825. https://doi.org/10.1093/nar/gkr223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Friedberg EC, Aguilera A, Gellert M, Hanawalt PC, Hays JB, Lehmann AR, Lindahl T, Lowndes N, Sarasin A, Wood RD (2006) DNA repair: from molecular mechanism to human disease. DNA Repair (Amst) 5:986–996

    Article  CAS  Google Scholar 

  10. Bunting SF, Nussenzweig A (2013) End-joining, translocations and cancer. Nat Rev Cancer 13:443–454. https://doi.org/10.1038/nrc3537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204. https://doi.org/10.1016/j.molcel.2010.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochim Biophys Acta 1786:139–152. https://doi.org/10.1016/j.bbcan.2008.07.005

    CAS  PubMed  Google Scholar 

  13. Corneo B, Wendland RL, Deriano L, Cui X, Klein IA, Wong SY, Arnal S, Holub AJ, Weller GR, Pancake BA, Shah S, Brandt VL, Meek K, Roth DB (2007) Rag mutations reveal robust alternative end joining. Nature 449:483–486. https://doi.org/10.1038/nature06168

    Article  CAS  PubMed  Google Scholar 

  14. Hefferin ML, Tomkinson AE (2005) Mechanism of DNA double-strand break repair by non-homologous end joining. DNA Repair (Amst) 4:639–648. https://doi.org/10.1016/j.dnarep.2004.12.005

    Article  CAS  Google Scholar 

  15. Jazayeri A, Jackson SP (2002) Screening the yeast genome for new DNA-repair genes. Genome Biol 3:REVIEWS1009

    Article  PubMed  PubMed Central  Google Scholar 

  16. Moore JK, Haber JE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16:2164–2173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wyman C, Kanaar R (2006) DNA double-strand break repair: all’s well that ends well. Annu Rev Genet 40:363–383. https://doi.org/10.1146/annurev.genet.40.110405.090451

    Article  CAS  PubMed  Google Scholar 

  18. Sharma S, Raghavan SC (2010) Nonhomologous DNA end joining in cell-free extracts. J Nucleic Acids. https://doi.org/10.4061/2010/389129

    PubMed Central  Google Scholar 

  19. Wang HC, Chou WC, Shieh SY, Shen CY (2006) Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Cancer Res 66:1391–1400. https://doi.org/10.1158/0008-5472.CAN-05-3270

    Article  CAS  PubMed  Google Scholar 

  20. Srivastava M, Nambiar M, Sharma S, Karki SS, Goldsmith G, Hegde M, Kumar S, Pandey M, Singh RK, Ray P, Natarajan R, Kelkar M, De A, Choudhary B, Raghavan SC (2012) An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell 151:1474–1487. https://doi.org/10.1016/j.cell.2012.11.054

    Article  CAS  PubMed  Google Scholar 

  21. Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211. https://doi.org/10.1146/annurev.biochem.052308.093131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vartak SV, Raghavan SC (2015) Inhibition of nonhomologous end joining to increase the specificity of CRISPR/Cas9 genome editing. FEBS J 282:4289–4294. https://doi.org/10.1111/febs.13416

    Article  CAS  PubMed  Google Scholar 

  23. Orthwein A, Fradet-Turcotte A, Noordermeer SM, Canny MD, Brun CM, Strecker J, Escribano-Diaz C, Durocher D (2014) Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 344:189–193. https://doi.org/10.1126/science.1248024

    Article  CAS  PubMed  Google Scholar 

  24. Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, Lobrich M (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16:715–724. https://doi.org/10.1016/j.molcel.2004.10.029

    Article  CAS  PubMed  Google Scholar 

  25. Deriano L, Roth DB (2013) Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet 47:433–455. https://doi.org/10.1146/annurev-genet-110711-155540

    Article  CAS  PubMed  Google Scholar 

  26. Tadi SK, Sebastian R, Dahal S, Babu RK, Choudhary B, Raghavan SC (2016) Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions. Mol Biol Cell 27:223–235. https://doi.org/10.1091/mbc.E15-05-0260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Holthofer H, Kretzler M, Haltia A, Solin ML, Taanman JW, Schagger H, Kriz W, Kerjaschki D, Schlondorff D (1999) Altered gene expression and functions of mitochondria in human nephrotic syndrome. FASEB J 13:523–532

    Article  CAS  PubMed  Google Scholar 

  28. Kren BT, Wong PY, Steer CJ (2003) Short, single-stranded oligonucleotides mediate targeted nucleotide conversion using extracts from isolated liver mitochondria. DNA Repair (Amst) 2:531–546

    Article  CAS  Google Scholar 

  29. Sage JM, Gildemeister OS, Knight KL (2010) Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J Biol Chem 285:18984–18990. https://doi.org/10.1074/jbc.M109.099846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen M, Liu B, Gao Q, Zhuo Y, Ge J (2011) Mitochondria-targeted peptide MTP-131 alleviates mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52:7027–7037. https://doi.org/10.1167/iovs.11-7524

    Article  CAS  PubMed  Google Scholar 

  31. Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 94:514–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hudson EK, Hogue BA, Souza-Pinto NC, Croteau DL, Anson RM, Bohr VA, Hansford RG (1998) Age-associated change in mitochondrial DNA damage. Free Radic Res 29:573–579

    Article  CAS  PubMed  Google Scholar 

  33. Hudson EK, Tsuchiya N, Hansford RG (1998) Age-associated changes in mitochondrial mRNA expression and translation in the Wistar rat heart. Mech Ageing Dev 103:179–193

    Article  CAS  PubMed  Google Scholar 

  34. Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286:774–779

    Article  CAS  PubMed  Google Scholar 

  35. Pakendorf B, Stoneking M (2005) Mitochondrial DNA and human evolution. Annu Rev Genomics Hum Genet 6:165–183. https://doi.org/10.1146/annurev.genom.6.080604.162249

    Article  CAS  PubMed  Google Scholar 

  36. Stierum RH, Croteau DL, Bohr VA (1999) Purification and characterization of a mitochondrial thymine glycol endonuclease from rat liver. J Biol Chem 274:7128–7136

    Article  CAS  PubMed  Google Scholar 

  37. Stierum RH, Dianov GL, Bohr VA (1999) Single-nucleotide patch base excision repair of uracil in DNA by mitochondrial protein extracts. Nucleic Acids Res 27:3712–3719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mason PA, Matheson EC, Hall AG, Lightowlers RN (2003) Mismatch repair activity in mammalian mitochondria. Nucleic Acids Res 31:1052–1058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Akbari M, Visnes T, Krokan HE, Otterlei M (2008) Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. DNA Repair (Amst) 7:605–616. https://doi.org/10.1016/j.dnarep.2008.01.002

    Article  CAS  Google Scholar 

  40. Liu P, Qian L, Sung JS, de Souza-Pinto NC, Zheng L, Bogenhagen DF, Bohr VA, Wilson DM 3rd, Shen B, Demple B (2008) Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria. Mol Cell Biol 28:4975–4987. https://doi.org/10.1128/MCB.00457-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Szczesny B, Tann AW, Longley MJ, Copeland WC, Mitra S (2008) Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 283:26349–26356. https://doi.org/10.1074/jbc.M803491200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. de Souza-Pinto NC, Mason PA, Hashiguchi K, Weissman L, Tian J, Guay D, Lebel M, Stevnsner TV, Rasmussen LJ, Bohr VA (2009) Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst) 8:704–719. https://doi.org/10.1016/j.dnarep.2009.01.021

    Article  Google Scholar 

  43. Jacobs HT, Lehtinen SK, Spelbrink JN (2000) No sex please, we’re mitochondria: a hypothesis on the somatic unit of inheritance of mammalian mtDNA. BioEssays 22:564–572. https://doi.org/10.1002/(SICI)1521-1878(200006)22:6<564:AID-BIES9>3.0.CO;2-4

    Article  CAS  PubMed  Google Scholar 

  44. D’Aurelio M, Gajewski CD, Lin MT, Mauck WM, Shao LZ, Lenaz G, Moraes CT, Manfredi G (2004) Heterologous mitochondrial DNA recombination in human cells. Hum Mol Genet 13:3171–3179. https://doi.org/10.1093/hmg/ddh326

    Article  PubMed  Google Scholar 

  45. Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, Quintanilla B (2013) The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. Cold Spring Harb Perspect Biol 5:a011080. https://doi.org/10.1101/cshperspect.a011080

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gilkerson RW, Schon EA, Hernandez E, Davidson MM (2008) Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation. J Cell Biol 181:1117–1128. https://doi.org/10.1083/jcb.200712101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Phillips AF, Millet AR, Tigano M, Dubois SM, Crimmins H, Babin L, Charpentier M, Piganeau M, Brunet E, Sfeir A (2017) Single-molecule analysis of mtDNA replication uncovers the basis of the common deletion. Mol Cell 65(527–538):e6. https://doi.org/10.1016/j.molcel.2016.12.014

    Google Scholar 

  48. Oppliger T, Wurgler FE, Sengstag C (1993) A plasmid system to monitor gene conversion and reciprocal recombination in vitro. Mutat Res 291:181–192

    Article  CAS  PubMed  Google Scholar 

  49. Raghavan SC, Raman MJ (2004) Nonhomologous end joining of complementary and noncomplementary DNA termini in mouse testicular extracts. DNA Repair (Amst) 3:1297–1310. https://doi.org/10.1016/j.dnarep.2004.04.007

    Article  CAS  Google Scholar 

  50. Sathees CR, Raman MJ (1999) Mouse testicular extracts process DNA double-strand breaks efficiently by DNA end-to-end joining. Mutat Res 433:1–13

    Article  CAS  PubMed  Google Scholar 

  51. Maianski NA, Geissler J, Srinivasula SM, Alnemri ES, Roos D, Kuijpers TW (2004) Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis. Cell Death Differ 11:143–153. https://doi.org/10.1038/sj.cdd.4401320

    Article  CAS  PubMed  Google Scholar 

  52. Chiruvella KK, Sebastian R, Sharma S, Karande AA, Choudhary B, Raghavan SC (2012) Time-dependent predominance of nonhomologous DNA end-joining pathways during embryonic development in mice. J Mol Biol 417:197–211. https://doi.org/10.1016/j.jmb.2012.01.029

    Article  CAS  PubMed  Google Scholar 

  53. Baumann P, West SC (1998) DNA end-joining catalyzed by human cell-free extracts. Proc Natl Acad Sci USA 95:14066–14070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Srivastava N, Raman MJ (2007) Homologous recombination-mediated double-strand break repair in mouse testicular extracts and comparison with different germ cell stages. Cell Biochem Funct 25:75–86. https://doi.org/10.1002/cbf.1375

    Article  CAS  PubMed  Google Scholar 

  55. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning a laboratory manual. Cold Spring Harbor Laboratory Press, New York

    Google Scholar 

  56. Sharma S, Choudhary B, Raghavan SC (2011) Efficiency of nonhomologous DNA end joining varies among somatic tissues, despite similarity in mechanism. Cell Mol Life Sci 68:661–676. https://doi.org/10.1007/s00018-010-0472-x

    Article  CAS  PubMed  Google Scholar 

  57. Kumar TS, Kari V, Choudhary B, Nambiar M, Akila TS, Raghavan SC (2010) Anti-apoptotic protein BCL2 down-regulates DNA end joining in cancer cells. J Biol Chem 285:32657–32670. https://doi.org/10.1074/jbc.M110.140350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kowalczykowski SC, Dixon DA, Eggleston AK, Lauder SD, Rehrauer WM (1994) Biochemistry of homologous recombination in Escherichia coli. Microbiol Rev 58:401–465

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW (1983) The double-strand-break repair model for recombination. Cell 33:25–35

    Article  CAS  PubMed  Google Scholar 

  60. Wallace DC (2005) The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene 354:169–180. https://doi.org/10.1016/j.gene.2005.05.001

    Article  CAS  PubMed  Google Scholar 

  61. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bohr VA (2002) Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32:804–812

    Article  CAS  PubMed  Google Scholar 

  63. Sykora P, Croteau DL, Bohr VA, Wilson DM 3rd (2011) Aprataxin localizes to mitochondria and preserves mitochondrial function. Proc Natl Acad Sci USA 108:7437–7442. https://doi.org/10.1073/pnas.1100084108

    Article  PubMed  PubMed Central  Google Scholar 

  64. Thyagarajan B, Campbell C (1997) Elevated homologous recombination activity in fanconi anemia fibroblasts. J Biol Chem 272:23328–23333

    Article  CAS  PubMed  Google Scholar 

  65. Dmitrieva NI, Malide D, Burg MB (2011) Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA. Am J Physiol Regul Integr Comp Physiol 301:R632–R640. https://doi.org/10.1152/ajpregu.00853.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kalifa L, Quintana DF, Schiraldi LK, Phadnis N, Coles GL, Sia RA, Sia EA (2012) Mitochondrial genome maintenance: roles for nuclear nonhomologous end-joining proteins in Saccharomyces cerevisiae. Genetics 190:951–964. https://doi.org/10.1534/genetics.111.138214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lakshmipathy U, Campbell C (1999) The human DNA ligase III gene encodes nuclear and mitochondrial proteins. Mol Cell Biol 19:3869–3876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chacinska A, Pfannschmidt S, Wiedemann N, Kozjak V, Sanjuan Szklarz LK, Schulze-Specking A, Truscott KN, Guiard B, Meisinger C, Pfanner N (2004) Essential role of Mia40 in import and assembly of mitochondrial intermembrane space proteins. EMBO J 23:3735–3746. https://doi.org/10.1038/sj.emboj.7600389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Barchiesi A, Wasilewski M, Chacinska A, Tell G, Vascotto C (2015) Mitochondrial translocation of APE1 relies on the MIA pathway. Nucleic Acids Res 43:5451–5464. https://doi.org/10.1093/nar/gkv433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lu L-Y, Yu X (2015) Double-strand break repair on sex chromosomes: challenges during male meiotic prophase. Cell Cycle 14(4):516–525. https://doi.org/10.1080/15384101.2014.998070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Johnson RD, Jasin M (2000) Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J 19:3398–3407. https://doi.org/10.1093/emboj/19.13.3398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jain S, Sugawara N, Haber JE (2016) Role of double-strand break end-tethering during gene conversion in Saccharomyces cerevisiae. PLoS Genet 12:e1005976. https://doi.org/10.1371/journal.pgen.1005976

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Prof. Mercy J. Raman, Dr. Mridula Nambiar, Dr. Monica Pandey, Dr. Supriya Vartak, Dipayan Ghosh and SCR Lab members for critical reading of the manuscript. We would like to thank Dr. Umesh Varshney, IISc for providing us Tg1 bacterial strain. We also would like to thank Dr. Ganesh Nagaraju, IISc for providing us with the TFAM antibody. We thank the Central Animal and Confocal facilities of the Indian Institute of Science for the help. Financial assistance from CSIR, New Delhi (37(1579)/13/EMR-II) and from IISc-DBT partnership programme [DBT/BF/PR/INS/2011-12/IISc] for SCR is acknowledged. SD is supported by fellowship from IISc, Bangalore (India).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sathees C. Raghavan.

Ethics declarations

Conflict of interest

The authors disclose that there is no potential conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 15159 kb)

Supplementary material 2 (DOC 35 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dahal, S., Dubey, S. & Raghavan, S.C. Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria. Cell. Mol. Life Sci. 75, 1641–1655 (2018). https://doi.org/10.1007/s00018-017-2702-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2702-y

Keywords

Navigation