Ku70型
基因组不稳定性
Ku80型
生物
癌症研究
DNA修复
癌变
细胞生长
细胞生物学
DNA损伤
癌症
遗传学
分子生物学
DNA
基因
DNA结合蛋白
转录因子
作者
Riadh Lobbardi,Jordan Pinder,Bárbara Martínez-Pastor,Marina Theodorou,Jessica S. Blackburn,Brian J. Abraham,Yuka Namiki,Marc R. Mansour,Nouran S. Abdelfattah,Aleksey Molodtsov,Gabriela Alexe,Debra Toiber,Manon de Waard,Esha Jain,Myriam Boukhali,Mattia Lion,Deepak Bhere,Khalid Shah,Alejandro Gutiérrez,Kimberly Stegmaier
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2017-10-04
卷期号:7 (11): 1336-1353
被引量:65
标识
DOI:10.1158/2159-8290.cd-17-0267
摘要
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation. Significance: TOX is an HMG box–containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability. Cancer Discov; 7(11); 1336–53. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1201
科研通智能强力驱动
Strongly Powered by AbleSci AI