HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome
Christopher Jenness, Simona Giunta, Manuel M. Müller, Hiroshi Kimura, Tom W. Muir, Hironori Funabiki
Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency–centro-meric instability–facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS–CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.
Published - Jan 30 2018
HELLS
Nucleosome remodeling
chromatin proteomics
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Variable Immunodeficiency syndrome Medicine & Life Sciences 100%
Nucleosomes Medicine & Life Sciences 66%
Chromatin Medicine & Life Sciences 50%
Aurora Kinase B Medicine & Life Sciences 21%
Mutation Medicine & Life Sciences 15%
Methyltransferases Medicine & Life Sciences 15%
Xenopus Medicine & Life Sciences 15%
Cerebral Palsy Medicine & Life Sciences 14%
Jenness, C., Giunta, S., Müller, M. M., Kimura, H., Muir, T. W., & Funabiki, H. (2018). HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome. Proceedings of the National Academy of Sciences of the United States of America, 115(5), E876-E885. https://doi.org/10.1073/pnas.1717509115
Jenness, Christopher ; Giunta, Simona ; Müller, Manuel M. et al. / HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 5. pp. E876-E885.
@article{33a29ea48e6d4e9fbfd592fdb7db80a3,
title = "HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome",
abstract = "Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency–centro-meric instability–facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS–CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.",
keywords = "HELLS, ICF, Nucleosome remodeling, Xenopus, chromatin proteomics",
author = "Christopher Jenness and Simona Giunta and M{\"u}ller, {Manuel M.} and Hiroshi Kimura and Muir, {Tom W.} and Hironori Funabiki",
note = "Funding Information: We thank N. Gamarra, R. Heald, T. Hirano, L. Langston (The Rockefeller University, New York, NY), G. Narlikar, M. O{\textquoteright}Donnell (The Rockefeller University), D. Remus (Memorial Sloan Kettering Cancer Center, New York, NY), and J. Walter for reagents; G. Narlikar and N. Gamarra for advice on nucleosome remodeling assays; H. Molina and J. Fernandez (Proteomics Resource Center for MS Analysis, The Rockefeller University) and C. Zierhut for helpful discussions; S. Ahmed, P. Choppakatla, and C. Zierhut for critical reading of the manuscript; and Naohito Nozaki (MAB Institute, Inc) for generating hybridoma cells. This work was supported by Grant R01GM075249 from the National Institutes of Health (to H.F.), Grants R37GM086868 and R01 GM107047 (to T.W.M.), a postdoctoral fellowship from the Swiss National Science Foundation (to M.M.M.), and Grants JP25116005 and JP26291071 from the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) (to H.K.). Funding Information: ACKNOWLEDGMENTS. We thank N. Gamarra, R. Heald, T. Hirano, L. Langston (The Rockefeller University, New York, NY), G. Narlikar, M. O{\textquoteright}Donnell (The Rockefeller University), D. Remus (Memorial Sloan Kettering Cancer Center, New York, NY), and J. Walter for reagents; G. Narlikar and N. Gamarra for advice on nucleosome remodeling assays; H. Molina and J. Fernandez (Proteomics Resource Center for MS Analysis, The Rockefeller University) and C. Zierhut for helpful discussions; S. Ahmed, P. Choppakatla, and C. Zierhut for critical reading of the manuscript; and Naohito Nozaki (MAB Institute, Inc) for generating hybridoma cells. This work was supported by Grant R01GM075249 from the National Institutes of Health (to H.F.), Grants R37GM086868 and R01 GM107047 (to T.W.M.), a postdoctoral fellowship from the Swiss National Science Foundation (to M.M.M.), and Grants JP25116005 and JP26291071 from the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) (to H.K.).",
pages = "E876--E885",
Jenness, C, Giunta, S, Müller, MM, Kimura, H, Muir, TW & Funabiki, H 2018, 'HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 5, pp. E876-E885. https://doi.org/10.1073/pnas.1717509115
HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome. / Jenness, Christopher; Giunta, Simona; Müller, Manuel M. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 5, 30.01.2018, p. E876-E885.
T1 - HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome
AU - Jenness, Christopher
AU - Giunta, Simona
AU - Müller, Manuel M.
AU - Kimura, Hiroshi
AU - Muir, Tom W.
AU - Funabiki, Hironori
N1 - Funding Information: We thank N. Gamarra, R. Heald, T. Hirano, L. Langston (The Rockefeller University, New York, NY), G. Narlikar, M. O'Donnell (The Rockefeller University), D. Remus (Memorial Sloan Kettering Cancer Center, New York, NY), and J. Walter for reagents; G. Narlikar and N. Gamarra for advice on nucleosome remodeling assays; H. Molina and J. Fernandez (Proteomics Resource Center for MS Analysis, The Rockefeller University) and C. Zierhut for helpful discussions; S. Ahmed, P. Choppakatla, and C. Zierhut for critical reading of the manuscript; and Naohito Nozaki (MAB Institute, Inc) for generating hybridoma cells. This work was supported by Grant R01GM075249 from the National Institutes of Health (to H.F.), Grants R37GM086868 and R01 GM107047 (to T.W.M.), a postdoctoral fellowship from the Swiss National Science Foundation (to M.M.M.), and Grants JP25116005 and JP26291071 from the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) (to H.K.). Funding Information: ACKNOWLEDGMENTS. We thank N. Gamarra, R. Heald, T. Hirano, L. Langston (The Rockefeller University, New York, NY), G. Narlikar, M. O'Donnell (The Rockefeller University), D. Remus (Memorial Sloan Kettering Cancer Center, New York, NY), and J. Walter for reagents; G. Narlikar and N. Gamarra for advice on nucleosome remodeling assays; H. Molina and J. Fernandez (Proteomics Resource Center for MS Analysis, The Rockefeller University) and C. Zierhut for helpful discussions; S. Ahmed, P. Choppakatla, and C. Zierhut for critical reading of the manuscript; and Naohito Nozaki (MAB Institute, Inc) for generating hybridoma cells. This work was supported by Grant R01GM075249 from the National Institutes of Health (to H.F.), Grants R37GM086868 and R01 GM107047 (to T.W.M.), a postdoctoral fellowship from the Swiss National Science Foundation (to M.M.M.), and Grants JP25116005 and JP26291071 from the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) (to H.K.).
N2 - Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency–centro-meric instability–facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS–CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.
AB - Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency–centro-meric instability–facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS–CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.
KW - HELLS
KW - ICF
KW - Nucleosome remodeling
KW - Xenopus
KW - chromatin proteomics
SP - E876-E885
Jenness C, Giunta S, Müller MM, Kimura H, Muir TW, Funabiki H. HELLS and CDCA7 comprise a bipartite nucleosome remodeling complex defective in ICF syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2018 Jan 30;115(5):E876-E885. doi: 10.1073/pnas.1717509115