Skip to main content

Thank you for visiting 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.

BAF complexes facilitate decatenation of DNA by topoisomerase IIα


Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies1,2, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure3 and the placement of Polycomb repressive complex 2 (PRC2) across the genome4,5. Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5–10% of childhood medulloblastomas6,7,8,9 and more than 15% of Burkitt’s lymphomas10,11. Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase IIα (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: BRG1 associates with TOP2A and regulates its function.
Figure 2: Expression of medulloblastoma-associated BRG1 mutants phenocopy TOP2A inhibition.
Figure 3: BRG1 facilitates the binding of TOP2A to chromatin in vivo through ATPase-dependent chromatin-remodelling activity.
Figure 4: TOP2A associates with the BAF complex through BAF250a.

Accession codes


Gene Expression Omnibus

Data deposits

The TOP2A ChIP-seq is deposited in the Gene Expression Omnibus (GEO) under accession number GSE45625.


  1. 1

    Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nature Genet. (5 May 2013)

  2. 2

    You, J. S. & Jones, P. A. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 22, 9–20 (2012)

    CAS  Article  Google Scholar 

  3. 3

    Clapier, C. R. & Cairns, B. R. The biology of chromatin remodeling complexes. Annu. Rev. Biochem. 78, 273–304 (2009)

    CAS  Article  Google Scholar 

  4. 4

    Ho, L. et al. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nature Cell Biol. 13, 903–913 (2011)

    CAS  Article  Google Scholar 

  5. 5

    Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316–328 (2010)

    CAS  Article  Google Scholar 

  6. 6

    Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Pugh, T. J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations within a broad landscape of genetic heterogeneity. Nature 488, 106–110 (2012)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Jones, D. T. W. et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 488, 100–105 (2012)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Robinson, G. et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 488, 43–48 (2012)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nature Genet. 44, 1321–1325 (2012)

    CAS  Article  Google Scholar 

  11. 11

    Richter, J. et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44, 1316–1320 (2012)

    CAS  Article  Google Scholar 

  12. 12

    Carpenter, A. J. & Porter, A. C. Construction, characterization, and complementation of a conditional-lethal DNA topoisomerase IIα mutant human cell line. Mol. Biol. Cell 15, 5700–5711 (2004)

    CAS  Article  Google Scholar 

  13. 13

    Lou, Z., Minter-Dykhouse, K. & Chen, J. BRCA1 participates in DNA decatenation. Nature Struct. Mol. Biol. 12, 589–593 (2005)

    CAS  Article  Google Scholar 

  14. 14

    Dawlaty, M. M. et al. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIα. Cell 133, 103–115 (2008)

    CAS  Article  Google Scholar 

  15. 15

    Ramamoorthy, M. et al. RECQL5 cooperates with Topoisomerase II alpha in DNA decatenation and cell cycle progression. Nucleic Acids Res. 40, 1621–1635 (2012)

    CAS  Article  Google Scholar 

  16. 16

    Ho, L. et al. An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc. Natl Acad. Sci. USA 106, 5181–5186 (2009)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Johnson, M., Phua, H. H., Bennett, S. C., Spence, J. M. & Farr, C. J. Studying vertebrate topoisomerase 2 function using a conditional knockdown system in DT40 cells. Nucleic Acids Res. 37, e98 (2009)

    Article  Google Scholar 

  18. 18

    Downes, C. S. et al. A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature 372, 467–470 (1994)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Luo, K., Yuan, J., Chen, J. & Lou, Z. Topoisomerase IIα controls the decatenation checkpoint. Nature Cell Biol. 11, 204–210 (2009)

    CAS  Article  Google Scholar 

  20. 20

    Sakaguchi, A. & Kikuchi, A. Functional compatibility between isoform α and β of type II DNA topoisomerase. J. Cell Sci. 117, 1047–1054 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Khavari, P. A., Peterson, C. L., Tamkun, J. W., Mendel, D. B. & Crabtree, G. R. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174 (1993)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Kool, M. et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 123, 473–484 (2012)

    CAS  Article  Google Scholar 

  23. 23

    Northcott, P. A. et al. Medulloblastomics: the end of the beginning. Nature Rev. Cancer 12, 818–834 (2012)

    CAS  Article  Google Scholar 

  24. 24

    Ho, L. et al. An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network. Proc. Natl Acad. Sci. USA 106, 5187–5191 (2009)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Stros, M., Bacikova, A., Polanska, E., Stokrova, J. & Strauss, F. HMGB1 interacts with human topoisomerase IIα and stimulates its catalytic activity. Nucleic Acids Res. 35, 5001–5013 (2007)

    CAS  Article  Google Scholar 

  26. 26

    Sano, K., Miyaji-Yamaguchi, M., Tsutsui, K. M. & Tsutsui, K. Topoisomerase IIβ activates a subset of neuronal genes that are repressed in AT-rich genomic environment. PLoS ONE 3, e4103 (2008)

    ADS  Article  Google Scholar 

  27. 27

    Capranico, G., Jaxel, C., Roberge, M., Kohn, K. W. & Pommier, Y. Nucleosome positioning as a critical determinant for the DNA cleavage sites of mammalian DNA topoisomerase II in reconstituted simian virus 40 chromatin. Nucleic Acids Res. 18, 4553–4559 (1990)

    CAS  Article  Google Scholar 

  28. 28

    Sperling, A. S., Jeong, K. S., Kitada, T. & Grunstein, M. Topoisomerase II binds nucleosome-free DNA and acts redundantly with topoisomerase I to enhance recruitment of RNA Pol II in budding yeast. Proc. Natl Acad. Sci. USA 108, 12693–12698 (2011)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Bourgo, R. J. et al. SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Mol. Biol. Cell 20, 3192–3199 (2009)

    CAS  Article  Google Scholar 

  30. 30

    Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J. & Medema, R. H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Bultman, S. J., Gebuhr, T. C. & Magnuson, T. A. Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in β-globin expression and erythroid development. Genes Dev. 19, 2849–2861 (2005)

    CAS  Article  Google Scholar 

  32. 32

    Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007)

    CAS  Article  Google Scholar 

  33. 33

    Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  34. 34

    Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

    CAS  Article  Google Scholar 

  36. 36

    Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002)

    CAS  Article  Google Scholar 

  37. 37

    Meyer, L. R. et al. The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res. 41, D64–D69 (2012)

    Article  Google Scholar 

Download references


We would like to acknowledge the DNA Sequencing Core facility of the National Heart, Lung, and Blood Institute (NHLBI) for sequencing the ChIP-seq libraries. This work was supported by the NIH (G.R.C.), The American Cancer Society (E.C.D.), The Helen Hay Whitney Foundation (D.C.H.) and the Division of Intramural Research program of NHLBI (K.Z.). G.R.C. is an investigator at the Howard Hughes Medical Institute.

Author information




E.C.D., D.C.H. and G.R.C. designed the experiments, and E.C.D. and D.C.H. performed the experiments. E.M. performed bioinformatic analysis. A.K., M.K., S.P. and Y-J.C. contributed human tumour samples. K.Z. and K.C. performed sequencing of the TOP2A ChIP. E.C.D., D.C.H. and G.R.C. wrote the manuscript.

Corresponding author

Correspondence to Gerald R. Crabtree.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-6. (PDF 2922 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dykhuizen, E., Hargreaves, D., Miller, E. et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIα. Nature 497, 624–627 (2013).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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