title: Disease mutant analysis identifies a new function of DAXX in telomerase regulation and telomere maintenance.
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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Mengfan
authors.initials: M
authors.lastname: Tang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Verna and Marrs Department of Biochemistry and Molecular biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Zaug
authors.affiliation: Verna and Marrs Department of Biochemistry and Molecular biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cech
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China mawenbin@mail.sysu.edu.cn songyang@bcm.edu.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ma
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education and State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China Verna and Marrs Department of Biochemistry and Molecular biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA mawenbin@mail.sysu.edu.cn songyang@bcm.edu.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Songyang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056970:Co-Repressor Proteins; D020541:Coiled Bodies / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018832:Molecular Chaperones; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D019098:Telomerase; D004265:DNA Helicases
keywords: Cancer; DAXX; Telomerase; Telomere