Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation

Cell Rep. 2014 Jul 10;8(1):297-310. doi: 10.1016/j.celrep.2014.05.050.

Edyta Marcon ¹, Zuyao Ni ¹, Shuye Pu ², Andrei L Turinsky ², Sandra Smiley Trimble ³, Jonathan B Olsen ³, Rosalind Silverman-Gavrila ⁴, Lorelei Silverman-Gavrila ⁵, Sadhna Phanse ¹, Hongbo Guo ¹, Guoqing Zhong ¹, Xinghua Guo ¹, Peter Young ¹, Swneke Bailey ⁶, Denitza Roudeva ³, Dorothy Zhao ³, Johannes Hewel ¹, Joyce Li ¹, Susanne Gräslund ⁷, Marcin Paduch ⁸, Anthony A Kossiakoff ⁸, Mathieu Lupien ⁹, Andrew Emili ¹⁰, Shoshana J Wodak ¹¹, Jack Greenblatt ¹²

Affiliations

1 Banting and Best Department of Medical Research, University of Toronto, CCBR, 160 College Street, Toronto, ON M5S 3E1, Canada.
2 Research Institute, Molecular Structure and Function Program, Hospital for Sick Children, 180 Dundas Street, Toronto, ON M5G 1Z8, Canada.
3 Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
4 Laboratory Medicine and Pathobiology Department, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
5 Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
6 Department of Medical Biophysics, University of Toronto, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada; The Princess Margaret Cancer Center, University Health Network, 610 University Avenue, Toronto, ON M5G 1L7, Canada.
7 Structural Genomics Consortium, University of Toronto, MaRS Centre, 101 College Street, Toronto, ON M5G 1L7, Canada.
8 Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
9 Department of Medical Biophysics, University of Toronto, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada; The Princess Margaret Cancer Center, University Health Network, 610 University Avenue, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON M5G 0A3, Canada.
10 Banting and Best Department of Medical Research, University of Toronto, CCBR, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
11 Research Institute, Molecular Structure and Function Program, Hospital for Sick Children, 180 Dundas Street, Toronto, ON M5G 1Z8, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
12 Banting and Best Department of Medical Research, University of Toronto, CCBR, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: jack.greenblatt@utoronto.ca.

PMID: 24981860 DOI: 10.1016/j.celrep.2014.05.050

Abstract

Chromatin regulation is driven by multicomponent protein complexes, which form functional modules. Deciphering the components of these modules and their interactions is central to understanding the molecular pathways these proteins are regulating, their functions, and their relation to both normal development and disease. We describe the use of affinity purifications of tagged human proteins coupled with mass spectrometry to generate a protein-protein interaction map encompassing known and predicted chromatin-related proteins. On the basis of 1,394 successful purifications of 293 proteins, we report a high-confidence (85% precision) network involving 11,464 protein-protein interactions among 1,738 different human proteins, grouped into 164 often overlapping protein complexes with a particular focus on the family of JmjC-containing lysine demethylases, their partners, and their roles in chromatin remodeling. We show that RCCD1 is a partner of histone H3K36 demethylase KDM8 and demonstrate that both are important for cell-cycle-regulated transcriptional repression in centromeric regions and accurate mitotic division.

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