title: A cancer-associated mutation inactivates a region of the high-mobility group protein HMG20b essential for cytokinesis.
abstract: Defects in the completion of cell division by cytokinesis have long been proposed to foster carcinogenesis by engendering chromosome instability, but few tumor suppressor mechanisms controlling this process have so far been identified. Here, we identify a carboxyl (C)-terminal region of the high-mobility group protein HMG20b that is essential for cytokinesis, and report that it is inactivated by a cancer-associated mutation. We find that a C-terminal region of HMG20b spanning residues 173-317 is necessary and sufficient not only for its localization to cytokinetic structures, but also for its interaction with the tumor suppressor BRCA2, implicated in the abscission step of cytokinesis. Indeed, expression of this C-terminal HMG20b region suffices to restore cytokinesis in HMG20b-depleted cells. The non-conservative substitution of HMG20b residue Ala247 with Pro, reported in human lung cancer, disrupts these activities of HMG20b, impairing cytokinesis in a trans-dominant manner. Our findings provide fresh insight into the mechanism by which the HMG20b-BRCA2 complex controls mitotic cell division, and implicate heterozygous HMG20b mutations affecting cytokinesis regulation in the genesis of human cancers.
authors.affiliation: a University of Cambridge ; Medical Research Council Cancer Unit; Hutchison/MRC Research Center ; Cambridge , UK.
authors.forename: MiYoung
authors.initials: M
authors.lastname: Lee
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
mesh_terms: D000409:Alanine; D024682:BRCA2 Protein / Q000378:metabolism*; D048749:Cytokinesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009154:Mutation; D011392:Proline
chemical_list: D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; C000625244:HMG20B protein, human; D006609:High Mobility Group Proteins; D011392:Proline; D000409:Alanine
keywords: A247P, alanine to proline substitution at position 247; BRCA2; BRCA2, breast cancer 2, early onset; COSMIC, Catalogue of Somatic Mutations in Cancer; Dox, doxycycline; EGFP, enhanced green fluorescent protein; ESCRT, endosomal sorting complex required for transport; GST, glutathione S-transferase; HMG, high mobility group; HMG20b; KLCC, kinesin-like coiled coil; Luc, luciferase; Tet, Tetracycline; UTR, untranslated regions; V312G, valine to glycine substitution at position 312; cytokinesis; somatic mutations in cancer; tumor suppression