TY - JOUR
T1 - BRCA1-interacting protein OLA1 requires interaction with BARD1 to regulate centrosome number
AU - Yoshino, Yuki
AU - Qi, Huicheng
AU - Fujita, Hiroki
AU - Shirota, Matsuyuki
AU - Abe, Shun
AU - Komiyama, Yuhei
AU - Shindo, Kazuha
AU - Nakayama, Masahiro
AU - Matsuzawa, Ayako
AU - Kobayashi, Akihiro
AU - Ogoh, Honami
AU - Watanabe, Toshio
AU - Ishioka, Chikashi
AU - Chiba, Natsuko
N1 - Funding Information:
This study was supported by grants-in-aid from JSPS KAKENHI grant numbers JP24300327 to N. Chiba and T. Watanabe, JP25640086 to N. Chiba, JP16H04690 to N. Chiba, T. Watanabe, and Y. Yoshino, Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) to C. Ishioka and N. Chiba, Program for Interdisciplinary Research in Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University to N. Chiba, Astellas Foundation for Research on Metabolic Disorders to N. Chiba, the Yasuda Medical Foundation to N. Chiba, the Princess Takamatsu Cancer Research Fund (14-24621) to N. Chiba, Daiwa Securities Health Foundation to N. Chiba, Kobayashi Foundation for Cancer Research to N. Chiba, Kobayashi International Scholarship Foundation to N. Chiba, Friends of Leukemia Research Fund to N. Chiba, the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University to T. Watanabe, and Research Program of the Smart-Aging Research Center, Tohoku University to N. Chiba.
Publisher Copyright:
© 2018 AACR.
PY - 2018/10
Y1 - 2018/10
N2 - BRCA1 functions as a tumor suppressor in DNA repair and centrosome regulation. Previously, Obg-like ATPase 1 (OLA1) was shown to interact with BARD1, a heterodimer partner of BRCA1. OLA1 binds to BRCA1, BARD1, and γ-tubulin and functions in centrosome regulation. This study determined that overexpression of wild-type OLA1 (OLA1-WT) caused centrosome amplification due to centriole overduplication in mammary tissue-derived cells. Centrosome amplification induced by overexpression of the cancer-derived OLA1mutant, which is deficient at regulating centrosome number, occurred in significantly fewer cells than in that induced by overexpression of OLA1-WT. Thus, it was hypothesized that overexpression of OLA1 with normal function efficiently induces centrosome amplification, but not that of OLA1 mutants, which are deficient at regulating centrosome number. We analyzed whether overexpression of OLA1 missense mutants of nine candidate phosphorylation residues, three residues modified with acetylation, and two ATP-binding residues caused centrosome amplification and identified five missense mutants that are deficient in the regulation of centrosome number. Three of themdid not bind to BARD1. Two phosphomimetic mutations restored the binding to BARD1 and the efficient centrosome amplification by their overexpression. Knockdown and overexpression of BARD1 also caused centrosome amplification. BARD1 mutant reported in cancer failed to bind to OLA1 and rescue the BARD1 knockdown-induced centrosome amplificationand reduced its centrosomal localization.Combined, these data reveal that the OLA1-BARD1 interaction is important for the regulation of centrosome number. Implications: Regulation of centrosome number by BRCA1/BARD1 together with OLA1 is important for the genome integrity to prevent tumor development.
AB - BRCA1 functions as a tumor suppressor in DNA repair and centrosome regulation. Previously, Obg-like ATPase 1 (OLA1) was shown to interact with BARD1, a heterodimer partner of BRCA1. OLA1 binds to BRCA1, BARD1, and γ-tubulin and functions in centrosome regulation. This study determined that overexpression of wild-type OLA1 (OLA1-WT) caused centrosome amplification due to centriole overduplication in mammary tissue-derived cells. Centrosome amplification induced by overexpression of the cancer-derived OLA1mutant, which is deficient at regulating centrosome number, occurred in significantly fewer cells than in that induced by overexpression of OLA1-WT. Thus, it was hypothesized that overexpression of OLA1 with normal function efficiently induces centrosome amplification, but not that of OLA1 mutants, which are deficient at regulating centrosome number. We analyzed whether overexpression of OLA1 missense mutants of nine candidate phosphorylation residues, three residues modified with acetylation, and two ATP-binding residues caused centrosome amplification and identified five missense mutants that are deficient in the regulation of centrosome number. Three of themdid not bind to BARD1. Two phosphomimetic mutations restored the binding to BARD1 and the efficient centrosome amplification by their overexpression. Knockdown and overexpression of BARD1 also caused centrosome amplification. BARD1 mutant reported in cancer failed to bind to OLA1 and rescue the BARD1 knockdown-induced centrosome amplificationand reduced its centrosomal localization.Combined, these data reveal that the OLA1-BARD1 interaction is important for the regulation of centrosome number. Implications: Regulation of centrosome number by BRCA1/BARD1 together with OLA1 is important for the genome integrity to prevent tumor development.
UR - http://www.scopus.com/inward/record.url?scp=85054315865&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054315865&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-0269
DO - 10.1158/1541-7786.MCR-18-0269
M3 - Article
C2 - 29858377
AN - SCOPUS:85054315865
VL - 16
SP - 1499
EP - 1511
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 10
ER -