BRCA1 interaction of centrosomal protein Nlp is required for successful mitotic progression.
Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic progression, although the underlying mechanism(s) remains to be further defined. Deficiency of BRCA1 function leads to disrupted mitotic machinery and genomic instability. Here, we show that BRCA1 physically interacts and colocalizes with Nlp, an important molecule involved in centrosome maturation and spindle formation. Interestingly, Nlp centrosomal localization and its protein stability are regulated by normal cellular BRCA1 function because cells containing BRCA1 mutations or silenced for endogenous BRCA1 exhibit disrupted Nlp colocalization to centrosomes and enhanced Nlp degradation. Its is likely that the BRCA1 regulation of Nlp stability involves Plk1 suppression. Inhibition of endogenous Nlp via the small interfering RNA approach results in aberrant spindle formation, aborted chromosomal segregation, and aneuploidy, which mimic the phenotypes of disrupted BRCA1. Thus, BRCA1 interaction of Nlp might be required for the successful mitotic progression, and abnormalities of Nlp lead to genomic instability.
Jin
Shunqian
S
State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Gao
Hua
H
Mazzacurati
Lucia
L
Wang
Yang
Y
Fan
Wenhong
W
Chen
Qiang
Q
Yu
Wei
W
Wang
Mingrong
M
Zhu
Xueliang
X
Zhang
Chuanmao
C
Zhan
Qimin
Q
D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D034741:RNA, Small Interfering
D019313:BRCA1 Protein; D008869:Microtubule-Associated Proteins; C476755:NINL protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering