Differential regulation of centrosome integrity by DNA damage response proteins
Differential regulation of centrosome integrity by DNA damage response proteins
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DOI：
10.4161/cc.7.14.6303
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发表时间：
2008-07-15
期刊：
影响因子：
4.3
通讯作者：
Lin, Shiaw-Yih
中科院分区：
文献类型：
--
作者：
Rai, Rekha;Phadnis, Ashwini;Lin, Shiaw-Yih
MDC 1和BRIT 1已被证明是响应DNA损伤的关键调节因子。然而，它们在中心体调控中的作用尚未阐明。在这项研究中，我们证明了这两个分子在调节中心体复制和有丝分裂的新功能。我们发现，MDC 1和BRIT 1是与γ-微管蛋白共定位的中心体的组成部分。任何一种蛋白质的缺失都会导致中心体扩增。然而，使它们保持中心体完整性的机制是不同的。MDC 1耗竭细胞表现出中心体过度复制，导致多极有丝分裂，染色体误分离，和非整倍性，而BRIT 1耗竭导致未对齐的纺锤体和/或落后的染色体与缺陷的纺锤体检查点激活，导致有缺陷的胞质分裂和多倍体。我们进一步说明了MDC 1和BRIT 1都是Aurora A和Plk 1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，MDC 1和BRIT 1的水平与人乳腺癌中的中心体扩增、有丝分裂缺陷和癌转移呈负相关。MDC 1和BRIT 1可能共同发挥肿瘤抑制基因的作用，至少部分是通过协调适当的中心体复制和有丝分裂纺锤体组装。
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.