title: Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation.
abstract: BubR1 acetylation is essential in mitosis. Mice heterozygous for the acetylation-deficient BubR1 allele (K243R/+) spontaneously developed tumors with massive chromosome missegregations. K243R/+ mouse embryonic fibroblasts (MEFs) exhibited a weakened spindle assembly checkpoint (SAC) with shortened mitotic timing. The generation of the SAC signal was intact, as Mad2 localization to the unattached kinetochore (KT) was unaltered; however, because of the premature degradation of K243R-BubR1, the mitotic checkpoint complex disassociated prematurely in the nocodazole-treated condition, suggesting that maintenance of the SAC is compromised. BubR1 acetylation was also required to counteract excessive Aurora B activity at the KT for stable chromosome-spindle attachments. The association of acetylation-deficient BubR1 with PP2A-B56α phosphatase was reduced, and the phosphorylated Ndc80 at the KT was elevated in K243R/+ MEFs. In relation, there was a marked increase of micronuclei and p53 mutation was frequently detected in primary tumors of K243R/+ mice. Collectively, the combined effects of failure in chromosome-spindle attachment and weakened SAC cause genetic instability and cancer in K243R/+ mice.
authors.affiliation: Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.
authors.forename: Inai
authors.initials: I
authors.lastname: Park
authors.forename: Hae-ock
authors.initials: HO
authors.lastname: Lee
authors.forename: Eunhee
authors.initials: E
authors.lastname: Choi
authors.forename: Yoo-Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kwon
authors.forename: Jaewon
authors.initials: J
authors.lastname: Min
authors.forename: Pil-Gu
authors.initials: PG
authors.lastname: Park
authors.forename: Seonju
authors.initials: S
authors.lastname: Lee
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.forename: Gyungyub
authors.initials: G
authors.lastname: Gong
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000483:Alleles; D000782:Aneuploidy; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development; D042822:Genomic Instability; D006579:Heterozygote; D018386:Kinetochores / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins; D051379:Mice; D057507:Mice, 129 Strain; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; C533103:Hec1 protein, mouse; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D008869:Microtubule-Associated Proteins; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases