Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance
Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance
复制标题
疾病突变分析确定了 DAXX 在端粒酶调节和端粒维持中的新功能
DOI：
10.1242/jcs.159467
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发表时间：
2015-01-15
影响因子：
4
通讯作者：
Zhou Songyang
中科院分区：
文献类型：
--
作者：
Tang, Mengfan;Li, Yujing;Zhou Songyang
摘要大多数人类癌症依赖于端粒酶来维持端粒，然而，约10%的癌症是端粒酶阴性的，并且利用端粒的替代延长（ALT）机制。DAXX基因的突变在端粒酶阳性和ALT细胞中经常被发现，DAXX突变如何导致癌症仍不清楚。我们在这里报告，内源性DAXX可以定位到Cajal小体，与端粒酶和调节端粒酶靶向端粒。此外，位于DAXX不同区域的疾病突变对DAXX与其结合伴侣相互作用的能力以及其靶向Cajal小体和端粒的能力产生差异性影响。此外，通过RNA干扰敲低DAXX导致端粒酶靶向端粒和端粒缩短减少。这些发现共同支持了DAXX为中心的端粒维持途径，其中DAXX与端粒酶的相互作用调节Cajal小体中的端粒酶组装和端粒酶靶向端粒。
ABSTRACT Most human cancers depend on the telomerase to maintain telomeres; however, about 10% of cancers are telomerase negative and utilize the alternative lengthening of telomeres (ALT) mechanism. Mutations in the DAXX gene have been found frequently in both telomerase-positive and ALT cells, and how DAXX mutations contribute to cancers remains unclear. We report here that endogenous DAXX can localize to Cajal bodies, associate with the telomerase and regulate telomerase targeting to telomeres. Furthermore, disease mutations that are located in different regions of DAXX differentially impact on its ability to interact with its binding partners and its targeting to Cajal bodies and telomeres. In addition, DAXX knockdown by RNA interference led to reduced telomerase targeting to telomeres and telomere shortening. These findings collectively support a DAXX-centric pathway for telomere maintenance, where DAXX interaction with the telomerase regulates telomerase assembly in Cajal bodies and telomerase targeting to telomeres.