title: Synuclein γ compromises spindle assembly checkpoint and renders resistance to antimicrotubule drugs.
abstract: Defects in the spindle assembly checkpoint (SAC) have been proposed to contribute to the chromosomal instability in human cancers. One of the major mechanisms underlying antimicrotubule drug (AMD) resistance involves acquired inactivation of SAC. Synuclein γ (SNCG), previously identified as a breast cancer-specific gene, is highly expressed in malignant cancer cells but not in normal epithelium. Here, we show that SNCG is sufficient to induce resistance to AMD-caused apoptosis in breast cancer cells and cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1 and inhibits its kinase activity. Specifically, the C-terminal (Gln106-Asp127) of SNCG binds to the N-terminal TPR (tetratricopeptidelike folds) motif of BubR1. SNCG-BubR1 interaction induces a structure change of BubR1, attenuates its interaction with other key checkpoint proteins of Cdc20, and thus compromises SAC function. SNCG expression in breast cancers from patients with a neoadjuvant clinical trial showed that SNCG-positive tumors are resistant to chemotherapy-induced apoptosis. These data show that SNCG renders AMD resistance by inhibiting BubR1 activity and attenuating SAC function.
authors.affiliation: Corresponding Authors: Yuenian Eric Shi, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China. daweieric@gmail.com.
authors.forename: Suyu
authors.initials: S
authors.lastname: Miao
authors.forename: Kejin
authors.initials: K
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Weng
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhu
authors.forename: Yunshu
authors.initials: Y
authors.lastname: Lu
authors.forename: Ramadas
authors.initials: R
authors.lastname: Krishna
authors.forename: Yuenian Eric
authors.initials: YE
authors.lastname: Shi
mesh_terms: D050256:Antimitotic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D008870:Microtubules / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D051845:gamma-Synuclein / Q000235:genetics*
chemical_list: D050256:Antimitotic Agents; D051845:gamma-Synuclein; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases