Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer.
Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer.
复制标题
Exosc 9启动SUMO依赖性lncRNA TERRA降解，影响内分泌治疗不敏感激素受体阳性乳腺癌的端粒完整性
作者：
长的非编码RNA（lncRNA）对于正常细胞生理学是不可或缺的，因此在人类细胞中受到严格的调控。然而，与mRNA不同的是，对lncRNA降解机制知之甚少。重要的是描绘lncRNA降解的调控，特别是对于含有lncRNA端粒重复序列的RNA（TERRA），因为TERRA-端粒R-环决定细胞周期进程和基因组稳定性。我们现在报告，外泌体复合物组分Exosc 9降解人类乳腺上皮细胞中的lncRNA TERRA。异染色质蛋白1 α（HP 1 α）将Exosc 9招募到端粒;具体而言，HP 1 α的SUMO修饰形式支持与Exosc 9和lncRNA TERRA的相互作用。Exosc 9的端粒富集是细胞周期依赖性的，并且与S/G2期中端粒TERRA的丢失一致。经常观察到Exosc 9升高，并驱动内分泌治疗抗性（ET-R）HR+乳腺癌（BCa）细胞的生长。具体而言，Exosc 9的敲低对ET-R细胞的端粒R环和染色体末端的完整性产生相反影响。因此，Exosc 9水平决定了DNA损伤和ET-R BCa细胞对PARP抑制剂的敏感性。在这方面，Exosc 9可以作为预测对PARP抑制剂作为ET-R HR+ BCa的靶向单药治疗的反应的有希望的生物标志物。
Long, noncoding RNAs (lncRNAs) are indispensable for normal cell physiology and, consequently, are tightly regulated in human cells. Yet, unlike mRNA, substantially less is known about the mechanisms for lncRNA degradation. It is important to delineate the regulatory control of lncRNA degradation, particularly for lncRNA telomeric repeat-containing RNA (TERRA), as the TERRA-telomere R-loops dictate cell cycle progression and genomic stability. We now report that the exosome complex component Exosc9 degrades lncRNA TERRA in human mammary epithelial cells. Heterochromatin protein 1 alpha (HP1α) recruits Exosc9 to the telomeres; specifically, the SUMO-modified form of HP1α supports interaction with Exosc9 and, as previously reported, lncRNA TERRA. The telomeric enrichment of Exosc9 is cell cycle-dependent and consistent with the loss of telomeric TERRA in the S/G2 phase. Elevated Exosc9 is frequently observed and drives the growth of endocrine therapy-resistant (ET-R) HR+ breast cancer (BCa) cells. Specifically, the knockdown of Exosc9 inversely impacts telomeric R-loops and the integrity of the chromosome ends of ET-R cells. Consistently, Exosc9 levels dictate DNA damage and the sensitivity of ET-R BCa cells to PARP inhibitors. In this regard, Exosc9 may serve as a promising biomarker for predicting the response to PARP inhibitors as a targeted monotherapy for ET-R HR+ BCa.
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影响因子：
64.5
作者：
Liu, Quansheng;Greimann, Jaclyn C.;Lima, Christopher D.
通讯作者：
Lima, Christopher D.
影响因子：
56.9
作者：
Azzalin, Claus M.;Reichenbach, Patrick;Lingner, Joachim
通讯作者：
Lingner, Joachim
DOI：
10.1186/s12964-020-00649-z
发表时间：
2020-09-18
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Bahnassy S;Thangavel H;Quttina M;Khan AF;Dhanyalayam D;Ritho J;Karami S;Ren J;Bawa-Khalfe T
通讯作者：
Bawa-Khalfe T
影响因子：
14.9
作者：
Mazzolini R;Gonzàlez N;Garcia-Garijo A;Millanes-Romero A;Peiró S;Smith S;García de Herreros A;Canudas S
通讯作者：
Canudas S
DOI：
10.1007/978-1-4939-6358-4_15
发表时间：
2016-01-01
期刊：
SUMO: METHODS AND PROTOCOLS
影响因子：
--
作者：
Bawa-Khalfe, Tasneem
通讯作者：
Bawa-Khalfe, Tasneem