Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells.
Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells.
复制标题
着丝粒组蛋白 H3 变体 CENP-A 的错误定位会导致人类细胞染色体不稳定 (CIN)。
DOI：
10.18632/oncotarget.18108
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Basrai MA
中科院分区：
文献类型：
--
作者：
Shrestha RL;Ahn GS;Staples MI;Sathyan KM;Karpova TS;Foltz DR;Basrai MA
染色体不稳定性（CIN）是许多癌症的标志，也是肿瘤发生的主要因素。着丝粒和动粒相关蛋白，如进化上保守的着丝粒组蛋白H3变体CENP-A，与着丝粒DNA结合以实现着丝粒功能和染色体稳定性。细胞CENP-A水平的严格调节防止其在酵母和果蝇中的错误定位以维持基因组稳定性。CENP-A过表达和错误定位在几种癌症中被观察到，并且据报道与侵袭性增加和预后不良相关。我们研究了是否有一个过表达CENP-A和CIN使用HeLa和染色体稳定的二倍体RPE 1细胞系作为模型系统的错误定位之间的直接关系。我们的研究结果表明，过度表达CENP-A的染色体臂的错误定位导致染色体的国会缺陷，落后的染色体，微核形成和有丝分裂出口的延迟。CENP-A过表达细胞显示着丝粒和动粒相关蛋白如CENP-C、CENP-T和Nuf 2的改变的定位，导致减弱的天然动粒，如通过减少的动粒间距离和CIN所示。重要的是，我们的结果表明，CENP-A到染色体臂的错误定位是CIN的主要贡献者之一，因为组蛋白伴侣DAXX的耗尽防止CENP-A错误定位并挽救CENP-A过表达细胞中减少的动粒间距离和CIN表型。总之，我们的结果证实CENP-A过表达和错误定位导致人类细胞中的CIN表型。这项研究提供了CENP-A过表达如何有助于癌症中的CIN的见解，并强调了了解防止CENP-A错误定位基因组稳定性的途径的重要性。
Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability.
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影响因子：
21.3
作者：
Carroll, Christopher W.;Silva, Mariana C. C.;Godek, Kristina M.;Jansen, Lars E. T.;Straight, Aaron F.
通讯作者：
Straight, Aaron F.
影响因子：
16
作者：
Hewawasam G;Shivaraju M;Mattingly M;Venkatesh S;Martin-Brown S;Florens L;Workman JL;Gerton JL
通讯作者：
Gerton JL
DOI：
10.1126/science.1259308
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Falk SJ;Guo LY;Sekulic N;Smoak EM;Mani T;Logsdon GA;Gupta K;Jansen LE;Van Duyne GD;Vinogradov SA;Lampson MA;Black BE
通讯作者：
Black BE
DOI：
10.1083/jcb.201001013
发表时间：
2010-06-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Carroll CW;Milks KJ;Straight AF
通讯作者：
Straight AF
影响因子：
64.5
作者：
Hori, Tetsuya;Amano, Miho;Fukagawa, Tatsuo
通讯作者：
Fukagawa, Tatsuo