Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance

• Published in: Journal of cell science Vol. 128; no. 2; pp. 331 - 341
• Main Authors: Tang, Mengfan, Li, Yujing, Zhang, Yi, Chen, Yuxi, Huang, Wenjun, Wang, Dan, Zaug, Arthur J, Liu, Dan, Zhao, Yong, Cech, Thomas R, Ma, Wenbin, Songyang, Zhou
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists 15.01.2015
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Coiled Bodies - genetics; Coiled Bodies - metabolism; DNA Helicases - genetics; Humans; In Situ Hybridization, Fluorescence; Mutation; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; RNA Interference; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; Telomere - metabolism; Telomere Homeostasis - genetics; DAXX; Telomerase; Telomere; Cancer
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.159467

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.