Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2

Autoři: Atiq Faramarz aff001;  Jesper A. Balk aff001;  Janne J. M. van Schie aff001;  Anneke B. Oostra aff001;  Cherien A. Ghandour aff001;  Martin A. Rooimans aff001;  Rob M. F. Wolthuis aff001;  Job de Lange aff001
Působiště autorů: Cancer Center Amsterdam, Department of Clinical Genetics, section Oncogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands aff001
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0220348


In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.

Klíčová slova:

Acetylation – Centromeres – DNA replication – Fibroblasts – Chromatids – Metaphase – Mitosis – Small interfering RNAs


1. Ciosk R, Shirayama M, Shevchenko A, Tanaka T, Toth A, Shevchenko A, et al. Cohesin's binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins. Mol Cell. 2000;5(2):243–54. doi: 10.1016/s1097-2765(00)80420-7 10882066.

2. Fernius J, Nerusheva OO, Galander S, Alves Fde L, Rappsilber J, Marston AL. Cohesin-dependent association of scc2/4 with the centromere initiates pericentromeric cohesion establishment. Curr Biol. 2013;23(7):599–606. doi: 10.1016/j.cub.2013.02.022 23499533; PubMed Central PMCID: PMC3627958.

3. Watrin E, Schleiffer A, Tanaka K, Eisenhaber F, Nasmyth K, Peters JM. Human Scc4 is required for cohesin binding to chromatin, sister-chromatid cohesion, and mitotic progression. Curr Biol. 2006;16(9):863–74. S0960-9822(06)01346-7 [pii]; doi: 10.1016/j.cub.2006.03.049 16682347

4. Kueng S, Hegemann B, Peters BH, Lipp JJ, Schleiffer A, Mechtler K, et al. Wapl controls the dynamic association of cohesin with chromatin. Cell. 2006;127(5):955–67. doi: 10.1016/j.cell.2006.09.040 17113138

5. Heidinger-Pauli JM, Unal E, Koshland D. Distinct targets of the Eco1 acetyltransferase modulate cohesion in S phase and in response to DNA damage. Mol Cell. 2009;34(3):311–21. doi: 10.1016/j.molcel.2009.04.008 19450529

6. Rowland BD, Roig MB, Nishino T, Kurze A, Uluocak P, Mishra A, et al. Building sister chromatid cohesion: smc3 acetylation counteracts an antiestablishment activity. Mol Cell. 2009;33(6):763–74. doi: 10.1016/j.molcel.2009.02.028 19328069

7. Nishiyama T, Ladurner R, Schmitz J, Kreidl E, Schleiffer A, Bhaskara V, et al. Sororin mediates sister chromatid cohesion by antagonizing Wapl. Cell. 2010;143(5):737–49. doi: 10.1016/j.cell.2010.10.031 21111234

8. Hauf S, Roitinger E, Koch B, Dittrich CM, Mechtler K, Peters JM. Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2. PLoS Biol. 2005;3(3):e69. doi: 10.1371/journal.pbio.0030069 15737063; PubMed Central PMCID: PMC1054881.

9. Waizenegger IC, Hauf S, Meinke A, Peters JM. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell. 2000;103(3):399–410. doi: 10.1016/s0092-8674(00)00132-x 11081627.

10. Zhang N, Panigrahi AK, Mao Q, Pati D. Interaction of Sororin protein with polo-like kinase 1 mediates resolution of chromosomal arm cohesion. J Biol Chem. 2011;286(48):41826–37. doi: 10.1074/jbc.M111.305888 21987589; PubMed Central PMCID: PMC3310079.

11. McGuinness BE, Hirota T, Kudo NR, Peters JM, Nasmyth K. Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells. PLoS Biol. 2005;3(3):e86. 04-PLBI-RA-0678R1 [pii]; doi: 10.1371/journal.pbio.0030086 15737064

12. Liu H, Rankin S, Yu H. Phosphorylation-enabled binding of SGO1-PP2A to cohesin protects sororin and centromeric cohesion during mitosis. Nat Cell Biol. 2013;15(1):40–9. ncb2637 [pii]; doi: 10.1038/ncb2637 23242214

13. Peters JM. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol. 2006;7(9):644–56. doi: 10.1038/nrm1988 16896351

14. Skibbens RV, Marzillier J, Eastman L. Cohesins coordinate gene transcriptions of related function within Saccharomyces cerevisiae. Cell Cycle. 2010;9(8):1601–6. doi: 10.4161/cc.9.8.11307 20404480; PubMed Central PMCID: PMC3096706.

15. Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008;132(3):422–33. doi: 10.1016/j.cell.2008.01.011 18237772.

16. Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008;451(7180):796–801. doi: 10.1038/nature06634 18235444.

17. Xu B, Sowa N, Cardenas ME, Gerton JL. L-leucine partially rescues translational and developmental defects associated with zebrafish models of Cornelia de Lange syndrome. Hum Mol Genet. 2015;24(6):1540–55. doi: 10.1093/hmg/ddu565 25378554; PubMed Central PMCID: PMC4351377.

18. Zakari M, Yuen K, Gerton JL. Etiology and pathogenesis of the cohesinopathies. Wiley Interdiscip Rev Dev Biol. 2015;4(5):489–504. doi: 10.1002/wdev.190 25847322.

19. Bose T, Lee KK, Lu S, Xu B, Harris B, Slaughter B, et al. Cohesin proteins promote ribosomal RNA production and protein translation in yeast and human cells. PLoS Genet. 2012;8(6):e1002749. doi: 10.1371/journal.pgen.1002749 PGENETICS-D-11-02119 [pii]. 22719263

20. Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet. 2004;36(6):631–5. doi: 10.1038/ng1364 15146186

21. Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet. 2004;36(6):636–41. doi: 10.1038/ng1363 15146185

22. Gillis LA, McCallum J, Kaur M, DeScipio C, Yaeger D, Mariani A, et al. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am J Hum Genet. 2004;75(4):610–23. doi: 10.1086/424698 15318302; PubMed Central PMCID: PMC1182048.

23. Musio A, Selicorni A, Focarelli ML, Gervasini C, Milani D, Russo S, et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006;38(5):528–30. doi: 10.1038/ng1779 16604071.

24. Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, et al. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007;80(3):485–94. doi: 10.1086/511888 17273969; PubMed Central PMCID: PMC1821101.

25. Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, et al. RAD21 Mutations Cause a Human Cohesinopathy. Am J Hum Genet. 2012.

26. Deardorff MA, Bando M, Nakato R, Watrin E, Itoh T, Minamino M, et al. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature. 2012.

27. Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanagihara I, Yamada M, et al. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet. 2005;37(5):468–70. doi: 10.1038/ng1548 15821733

28. van der Lelij P, Chrzanowska KH, Godthelp BC, Rooimans MA, Oostra AB, Stumm M, et al. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am J Hum Genet. 2010;86(2):262–6. doi: 10.1016/j.ajhg.2010.01.008 20137776

29. Chetaille P, Preuss C, Burkhard S, Cote JM, Houde C, Castilloux J, et al. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet. 2014;46(11):1245–9. doi: 10.1038/ng.3113 25282101.

30. Castronovo P, Gervasini C, Cereda A, Masciadri M, Milani D, Russo S, et al. Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome. Chromosome Res. 2009;17(6):763–71. doi: 10.1007/s10577-009-9066-6 19690971.

31. Banerji R, Eble DM, Iovine MK, Skibbens RV. Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin. Dev Dyn. 2016;245(1):7–21. doi: 10.1002/dvdy.24354 26434741.

32. Remeseiro S, Cuadrado A, Losada A. Cohesin in development and disease. Development. 2013;140(18):3715–8. doi: 10.1242/dev.090605 23981654.

33. Skibbens RV, Colquhoun JM, Green MJ, Molnar CA, Sin DN, Sullivan BJ, et al. Cohesinopathies of a feather flock together. PLoS Genet. 2013;9(12):e1004036. doi: 10.1371/journal.pgen.1004036 24367282; PubMed Central PMCID: PMC3868590.

34. Hou F, Zou H. Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister-chromatid cohesion. Mol Biol Cell. 2005;16(8):3908–18. doi: 10.1091/mbc.E04-12-1063 15958495

35. Whelan G, Kreidl E, Wutz G, Egner A, Peters JM, Eichele G. Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin. EMBO J. 2011.

36. van der Lelij P, Godthelp BC, vZ W., vG D., Oostra AB, Steltenpool J, et al. The cellular phenotype of Roberts syndrome fibroblasts as revealed by ectopic expression of ESCO2. PLoS One. 2009;4(9):e6936. doi: 10.1371/journal.pone.0006936 19738907

37. Moldovan GL, Pfander B, Jentsch S. PCNA controls establishment of sister chromatid cohesion during S phase. Mol Cell. 2006;23(5):723–32. doi: 10.1016/j.molcel.2006.07.007 16934511

38. Ivanov MP, Ladurner R, Poser I, Beveridge R, Rampler E, Hudecz O, et al. The replicative helicase MCM recruits cohesin acetyltransferase ESCO2 to mediate centromeric sister chromatid cohesion. EMBO J. 2018;37(15). Epub 2018/06/23. doi: 10.15252/embj.201797150 29930102; PubMed Central PMCID: PMC6068434.

39. Minamino M, Tei S, Negishi L, Kanemaki MT, Yoshimura A, Sutani T, et al. Temporal Regulation of ESCO2 Degradation by the MCM Complex, the CUL4-DDB1-VPRBP Complex, and the Anaphase-Promoting Complex. Curr Biol. 2018;28(16):2665–72 e5. Epub 2018/08/14. doi: 10.1016/j.cub.2018.06.037 30100344.

40. Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV. Cohesin acetylation speeds the replication fork. Nature. 2009;462(7270):231–4. doi: 10.1038/nature08550 19907496

41. Minamino M, Ishibashi M, Nakato R, Akiyama K, Tanaka H, Kato Y, et al. Esco1 Acetylates Cohesin via a Mechanism Different from That of Esco2. Curr Biol. 2015;25(13):1694–706. doi: 10.1016/j.cub.2015.05.017 26051894.

42. Kawasumi R, Abe T, Arakawa H, Garre M, Hirota K, Branzei D. ESCO1/2's roles in chromosome structure and interphase chromatin organization. Genes Dev. 2017;31(21):2136–50. doi: 10.1101/gad.306084.117 29196537; PubMed Central PMCID: PMC5749162.

43. Alomer RM, da Silva EML, Chen J, Piekarz KM, McDonald K, Sansam CG, et al. Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression. Proc Natl Acad Sci U S A. 2017;114(37):9906–11. doi: 10.1073/pnas.1708291114 28847955; PubMed Central PMCID: PMC5604028.

44. Wu Y, Brosh RM Jr., DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster. Nucleic Acids Res. 2012;40(10):4247–60. doi: 10.1093/nar/gks039 22287629; PubMed Central PMCID: PMC3378879.

45. Pisani FM, Napolitano E, Napolitano LMR, Onesti S. Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11. Genes (Basel). 2018;9(11). doi: 10.3390/genes9110564 30469382; PubMed Central PMCID: PMC6266566.

46. Rudra S, Skibbens RV. Sister chromatid cohesion establishment occurs in concert with lagging strand synthesis. Cell Cycle. 2012;11(11):2114–21. doi: 10.4161/cc.20547 22592531

47. Petronczki M, Chwalla B, Siomos MF, Yokobayashi S, Helmhart W, Deutschbauer AM, et al. Sister-chromatid cohesion mediated by the alternative RF-CCtf18/Dcc1/Ctf8, the helicase Chl1 and the polymerase-alpha-associated protein Ctf4 is essential for chromatid disjunction during meiosis II. J Cell Sci. 2004;117(Pt 16):3547–59. doi: 10.1242/jcs.01231 15226378

48. Mayer ML, Pot I, Chang M, Xu H, Aneliunas V, Kwok T, et al. Identification of protein complexes required for efficient sister chromatid cohesion. Mol Biol Cell. 2004;15(4):1736–45. doi: 10.1091/mbc.E03-08-0619 14742714; PubMed Central PMCID: PMC379271.

49. Cali F, Bharti SK, Di Perna R, Brosh RM Jr., Pisani FM. Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway. Nucleic Acids Res. 2016;44(2):705–17. doi: 10.1093/nar/gkv1112 26503245; PubMed Central PMCID: PMC4737141.

50. Cortone G, Zheng G, Pensieri P, Chiappetta V, Tate R, Malacaria E, et al. Interaction of the Warsaw breakage syndrome DNA helicase DDX11 with the replication fork-protection factor Timeless promotes sister chromatid cohesion. PLoS Genet. 2018;14(10):e1007622. doi: 10.1371/journal.pgen.1007622 30303954; PubMed Central PMCID: PMC6179184.

51. Samora CP, Saksouk J, Goswami P, Wade BO, Singleton MR, Bates PA, et al. Ctf4 Links DNA Replication with Sister Chromatid Cohesion Establishment by Recruiting the Chl1 Helicase to the Replisome. Mol Cell. 2016;63(3):371–84. doi: 10.1016/j.molcel.2016.05.036 27397686; PubMed Central PMCID: PMC4980427.

52. Borges V, Smith DJ, Whitehouse I, Uhlmann F. An Eco1-independent sister chromatid cohesion establishment pathway in S. cerevisiae. Chromosoma. 2013.

53. Chen Z, McCrosky S, Guo W, Li H, Gerton JL. A Genetic Screen to Discover Pathways Affecting Cohesin Function in Schizosaccharomyces pombe Identifies Chromatin Effectors. G3 (Bethesda). 2012;2(10):1161–8.

54. Skibbens RV. Chl1p, a DNA helicase-like protein in budding yeast, functions in sister-chromatid cohesion. Genetics. 2004;166(1):33–42. doi: 10.1534/genetics.166.1.33 15020404

55. Abe T, Kawasumi R, Arakawa H, Hori T, Shirahige K, Losada A, et al. Chromatin determinants of the inner-centromere rely on replication factors with functions that impart cohesion. Oncotarget. 2016;7(42):67934–47. doi: 10.18632/oncotarget.11982 27636994; PubMed Central PMCID: PMC5356530.

56. van der Lelij P, Oostra AB, Rooimans MA, Joenje H, de Winter JP. Diagnostic Overlap between Fanconi Anemia and the Cohesinopathies: Roberts Syndrome and Warsaw Breakage Syndrome. Anemia. 2010;2010:565268. doi: 10.1155/2010/565268 21490908

57. de Lange J, Faramarz A, Oostra AB, de Menezes RX, van der Meulen IH, Rooimans MA, et al. Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. Nat Commun. 2015;6:8399. ncomms9399 [pii]; doi: 10.1038/ncomms9399 26423134

58. Daum JR, Potapova TA, Sivakumar S, Daniel JJ, Flynn JN, Rankin S, et al. Cohesion fatigue induces chromatid separation in cells delayed at metaphase. Curr Biol. 2011;21(12):1018–24. S0960-9822(11)00588-4 [pii]; doi: 10.1016/j.cub.2011.05.032 21658943

59. Stevens D, Gassmann R, Oegema K, Desai A. Uncoordinated loss of chromatid cohesion is a common outcome of extended metaphase arrest. PLoS One. 2011;6(8):e22969. doi: 10.1371/journal.pone.0022969 PONE-D-11-09005 [pii]. 21829677

60. Cota CD, Garcia-Garcia MJ. The ENU-induced cetus mutation reveals an essential role of the DNA helicase DDX11 for mesoderm development during early mouse embryogenesis. Dev Dyn. 2012;241(8):1249–59. Epub 2012/06/09. doi: 10.1002/dvdy.23810 22678773.

61. Inoue A, Li T, Roby SK, Valentine MB, Inoue M, Boyd K, et al. Loss of ChlR1 helicase in mouse causes lethality due to the accumulation of aneuploid cells generated by cohesion defects and placental malformation. Cell Cycle. 2007;6(13):1646–54. 4411 [pii]. doi: 10.4161/cc.6.13.4411 17611414

62. Ding H, Guo M, Vidhyasagar V, Talwar T, Wu Y. The Q Motif Is Involved in DNA Binding but Not ATP Binding in ChlR1 Helicase. PLoS One. 2015;10(10):e0140755. doi: 10.1371/journal.pone.0140755 26474416; PubMed Central PMCID: PMC4608764.

63. Murayama Y, Samora CP, Kurokawa Y, Iwasaki H, Uhlmann F. Establishment of DNA-DNA Interactions by the Cohesin Ring. Cell. 2018;172(3):465–77 e15. doi: 10.1016/j.cell.2017.12.021 29358048; PubMed Central PMCID: PMC5786502.

64. Gandhi R, Gillespie PJ, Hirano T. Human Wapl is a cohesin-binding protein that promotes sister-chromatid resolution in mitotic prophase. Curr Biol. 2006;16(24):2406–17. doi: 10.1016/j.cub.2006.10.061 17112726

65. Vega H, Trainer AH, Gordillo M, Crosier M, Kayserili H, Skovby F, et al. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. J Med Genet. 2010;47(1):30–7. doi: 10.1136/jmg.2009.068395 19574259

66. Bharti SK, Khan I, Banerjee T, Sommers JA, Wu Y, Brosh RM Jr. Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome. Cell Mol Life Sci. 2014;71(14):2625–39. doi: 10.1007/s00018-014-1569-4 24487782

67. Wu Y, Sommers J, Khan I, dW J., Brosh R. Biochemical characterization of Warsaw Breakage Syndrome helicase. J Biol Chem. 2011.

68. Benedict B, van Schie J, Oostra A, Balk J, Wolthuis R, te Riele H, et al. WAPL-dependent repair of damaged replication forks underlies oncogene-induced loss of sister chromatid cohesion. submitted manuscript. 2019.

69. Srinivasan M, Petela NJ, Scheinost JC, Collier J, Voulgaris M, M BR, et al. Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1. Elife. 2019;8. Epub 2019/06/22. doi: 10.7554/eLife.44736 31225797; PubMed Central PMCID: PMC6588348.

70. Xu H, Boone C, Brown GW. Genetic dissection of parallel sister-chromatid cohesion pathways. Genetics. 2007;176(3):1417–29. doi: 10.1534/genetics.107.072876 17483413

71. Hermsen MA, Joenje H, Arwert F, Welters MJ, Braakhuis BJ, Bagnay M, et al. Centromeric breakage as a major cause of cytogenetic abnormalities in oral squamous cell carcinoma. Genes Chromosomes Cancer. 1996;15(1):1–9. doi: 10.1002/(SICI)1098-2264(199601)15:1<1::AID-GCC1>3.0.CO;2-8 8824719

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