Abstract
Nucleosomal DNA is arranged in a higher-order structure that presents a barrier to most cellular processes involving protein DNA interactions1. The cellular machinery involved in sister chromatid cohesion, the cohesin complex, also requires access to the nucleosomal DNA to perform its function in chromosome segregation2,3,4,5,6,7,8,9,10. The machineries that provide this accessibility are termed chromatin remodelling factors11. Here, we report the isolation of a human ISWI (SNF2h)-containing chromatin remodelling complex that encompasses components of the cohesin and NuRD complexes. We show that the hRAD21 subunit of the cohesin complex directly interacts with the ATPase subunit SNF2h. Mapping of hRAD21, SNF2h and Mi2 binding sites by chromatin immunoprecipitation experiments reveals the specific association of these three proteins with human DNA elements containing Alu sequences. We find a correlation between modification of histone tails and association of the SNF2h/cohesin complex with chromatin. Moreover, we show that the association of the cohesin complex with chromatin can be regulated by the state of DNA methylation. Finally, we present evidence pointing to a role for the ATPase activity of SNF2h in the loading of hRAD21 on chromatin.
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References
Kornberg, R. D. & Lorch, Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294 (1999)
Larionov, V. L., Karpova, T. S., Kouprina, N. Y. & Jouravleva, G. A. A mutant of Saccharomyces cerevisiae with impaired maintenance of centromeric plasmids. Curr. Genet. 10, 15–20 (1985)
Strunnikov, A. V., Larionov, V. L. & Koshland, D. SMC1: an essential yeast gene encoding a putative head-rod-tail protein is required for nuclear division and defines a new ubiquitous protein family. J. Cell Biol. 123, 1635–1648 (1993)
Michaelis, C., Ciosk, R. & Nasmyth, K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35–45 (1997)
Guacci, V., Koshland, D. & Strunnikov, A. A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell 91, 47–57 (1997)
Birkenbihl, R. P. & Subramani, S. Cloning and characterization of rad21, an essential gene of Schizosaccharomyces pombe involved in DNA double-strand-break repair. Nucleic Acids Res. 20, 6605–6611 (1992)
Birkenbihl, R. P. & Subramani, S. The rad21 gene product of Schizosaccharomyces pombe is a nuclear, cell cycle-regulated phosphoprotein. J. Biol. Chem. 270, 7703–7711 (1995)
Tatebayashi, K., Kato, J. & Ikeda, H. Isolation of a Schizosaccharomyces pombe rad21ts mutant that is aberrant in chromosome segregation, microtubule function, DNA repair and sensitive to hydroxyurea: possible involvement of Rad21 in ubiquitin-mediated proteolysis. Genetics 148, 49–57 (1998)
Tomonaga, T. et al. Characterization of fission yeast cohesin: essential anaphase proteolysis of Rad21 phosphorylated in the S phase. Genes Dev. 14, 2757–2770 (2000)
Schmiesing, J. A. et al. Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics. Proc. Natl Acad. Sci. USA 95, 12906–12911 (1998)
Fyodorov, D. V. & Kadonaga, J. T. The many faces of chromatin remodeling: SWItching beyond transcription. Cell 106, 523–525 (2001)
Bochar, D. A. et al. A family of chromatin remodeling factors related to Williams syndrome transcription factor. Proc. Natl Acad. Sci. USA 97, 1038–1043 (2000)
Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998)
Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell. 2, 851–861 (1998)
Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998)
Waizenegger, I. C., Hauf, S., Meinke, A. & Peters, J. M. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 103, 399–410 (2000)
Uhlmann, F., Lottspeich, F. & Nasmyth, K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc 1. Nature 400, 37–42 (1999)
Mighell, A. J., Markham, A. F. & Robinson, P. A. Alu sequences. FEBS Lett. 417, 1–5 (1997)
Schmid, C. W. Does SINE evolution preclude Alu function? Nucleic Acids Res. 26, 4541–4550 (1998)
Hellmann-Blumberg, U., Hintz, M. F., Gatewood, J. M. & Schmid, C. W. Developmental differences in methylation of human Alu repeats. Mol. Cell Biol. 13, 4523–4530 (1993)
Broday, L., Lee, Y. W. & Costa, M. 5-azacytidine induces transgene silencing by DNA methylation in Chinese hamster cells. Mol. Cell Biol. 19, 3198–3204 (1999)
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)
Gelbart, M. E., Rechsteiner, T., Richmond, T. J. & Tsukiyama, T. Interactions of Isw2 chromatin remodeling complex with nucleosomal arrays: analyses using recombinant yeast histones and immobilized templates. Mol. Cell Biol. 21, 2098–2106 (2001)
Bochar, D. A. et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257–265 (2000)
Hakimi, M. A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002)
Lai, J.-S. & Herr, W. Ethidium bromide provides a simple tool for identifying genuine DNA-independent protein associations. Proc. Natl Acad. Sci. USA 89, 6958–6962 (1992)
Stoger, R. et al. Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell 73, 61–71 (1993)
Acknowledgements
We thank W. Wang and G. Mandel for the gift of Mi2 and REST antibodies, respectively. We also thank T. Nagase at the Kazusa DNA Research Institute in Japan for providing the hRAD21 cDNA. We also thank H. C. Gregson and A. R. Ball, Jr for analysis of Rad21 and SNF2h interactions. This work was supported by a grant from NIH to R.S. and in part by a March of Dimes Basil O'Conner Scholarship and the NIH to K.Y. K.Y. is a Scholar of the Leukemia & Lymphoma Society. M.-A.H. was supported by a postdoctoral fellowship from Association pour la Recherche sur le Cancer (FRANCE). D.A.B. is a recipient of an NIH training grant.
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Hakimi, MA., Bochar, D., Schmiesing, J. et al. A chromatin remodelling complex that loads cohesin onto human chromosomes. Nature 418, 994–998 (2002). https://doi.org/10.1038/nature01024
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DOI: https://doi.org/10.1038/nature01024
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