CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity.
CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity.
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DOI：
10.1083/jcb.202007195
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发表时间：
2021-04-05
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;Rossi A;Wangsa D;Hogan AK;Zaldana KS;Suva E;Chung YJ;Sanders CL;Difilippantonio S;Karpova TS;Karim B;Foltz DR;Fachinetti D;Aplan PD;Ried T;Basrai MA
将CENP-A定位于着丝粒是防止染色体不稳定(CIN)的关键。CENP-A在几种癌症中过度表达和错误定位。Shrestha等人。表明CENP-A的过度表达导致其错误定位、CIN和具有核型异质性的非整倍体。染色体不稳定(CIN)是许多癌症的标志。将着丝粒的组蛋白H3变异体CENP-A限制在着丝粒上可以预防CIN。CENP-A过度表达(OE)和错位定位已在肿瘤中观察到，并与预后不良相关；然而，CENP-A OE对CIN和非整倍体的分子后果尚未确定。在这里，我们发现CENP-A OE导致其错误定位和CIN，在假二倍体DLD1细胞和异种移植小鼠模型中，CIN具有落后的染色体和微核。CIN是由于蛋白质在动粒上的定位减少，导致动粒完整性的缺陷和不稳定的动粒-微管连接。CENP-A OE导致DLD1细胞黏附基因表达减少，侵袭力增强。我们发现CENP-A OE有助于人类细胞和异种移植小鼠模型中具有核型异质性的非整倍体。综上所述，我们的结果提供了CENP-A OE和非整倍体之间的分子联系，并提示核型异质性可能有助于CENP-A过表达的癌症的侵袭性表型。
Restricting the localization of CENP-A to centromeres is essential to prevent chromosomal instability (CIN). CENP-A is overexpressed and mislocalized in several cancers. Shrestha et al. show that overexpression of CENP-A leads to its mislocalization, CIN, and aneuploidy with karyotypic heterogeneity. Chromosomal instability (CIN) is a hallmark of many cancers. Restricting the localization of centromeric histone H3 variant CENP-A to centromeres prevents CIN. CENP-A overexpression (OE) and mislocalization have been observed in cancers and correlate with poor prognosis; however, the molecular consequences of CENP-A OE on CIN and aneuploidy have not been defined. Here, we show that CENP-A OE leads to its mislocalization and CIN with lagging chromosomes and micronuclei in pseudodiploid DLD1 cells and xenograft mouse model. CIN is due to reduced localization of proteins to the kinetochore, resulting in defects in kinetochore integrity and unstable kinetochore–microtubule attachments. CENP-A OE contributes to reduced expression of cell adhesion genes and higher invasion of DLD1 cells. We show that CENP-A OE contributes to aneuploidy with karyotypic heterogeneity in human cells and xenograft mouse model. In summary, our results provide a molecular link between CENP-A OE and aneuploidy, and suggest that karyotypic heterogeneity may contribute to the aggressive phenotype of CENP-A–overexpressing cancers.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
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：
10.5
作者：
Deyter GM;Biggins S
通讯作者：
Biggins S