Rai Rekha, Phadnis Ashwini, Haralkar Sharda, Badwe Rajendra A, Dai Hui, Li Kaiyi, Lin Shiaw-Yih
Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India.
Cell Cycle. 2008 Jul 15;7(14):2225-33. doi: 10.4161/cc.7.14.6303. Epub 2008 May 14.
MDC1 and BRIT1 have been shown to function as key regulators in response to DNA damage. However, their roles in centrosomal regulation haven't been elucidated. In this study, we demonstrated the novel functions of these two molecules in regulating centrosome duplication and mitosis. We found that MDC1 and BRIT1 were integral components of the centrosome that colocalize with gamma-tubulin. Depletion of either protein led to centrosome amplification. However, the mechanisms that allow them to maintain centrosome integrity are different. MDC1-depleted cells exhibited centrosome overduplication, leading to multipolar mitosis, chromosome missegregation, and aneuploidy, whereas BRIT1 depletion led to misaligned spindles and/or lagging chromosomes with defective spindle checkpoint activation that resulted in defective cytokinesis and polyploidy. We further illustrated that both MDC1 and BRIT1 were negative regulators of Aurora A and Plk1, two centrosomal kinases involved in centrosome maturation and spindle assembly. Moreover, the levels of MDC1 and BRIT1 inversely correlated with centrosome amplification, defective mitosis and cancer metastasis in human breast cancer. Together, MDC1 and BRIT1 may function as tumor-suppressor genes, at least in part by orchestrating proper centrosome duplication and mitotic spindle assembly.
MDC1和BRIT1已被证明在应对DNA损伤时作为关键调节因子发挥作用。然而，它们在中心体调节中的作用尚未阐明。在本研究中，我们证明了这两种分子在调节中心体复制和有丝分裂中的新功能。我们发现MDC1和BRIT1是中心体的组成成分，与γ-微管蛋白共定位。任一蛋白的缺失都会导致中心体扩增。然而，它们维持中心体完整性的机制不同。MDC1缺失的细胞表现出中心体过度复制，导致多极有丝分裂、染色体错分离和非整倍体，而BRIT1缺失则导致纺锤体排列异常和/或染色体滞后，纺锤体检查点激活缺陷，从而导致胞质分裂缺陷和多倍体。我们进一步阐明，MDC1和BRIT1都是Aurora A和Plk1的负调节因子，这两种中心体激酶参与中心体成熟和纺锤体组装。此外，在人类乳腺癌中，MDC1和BRIT1的水平与中心体扩增、有丝分裂缺陷和癌症转移呈负相关。总之，MDC1和BRIT1可能至少部分通过协调适当的中心体复制和有丝分裂纺锤体组装而作为肿瘤抑制基因发挥作用。
