期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 17, 页码 3982-3989出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.128512
关键词
Telomere; HMBOX1; TAH1; Homeobox; DNA damage response; Alternative lengthening of telomeres; ALT pathway
类别
资金
- National Basic Research Program (973 Program) [2012CB911201, 2010CB945401]
- National Natural Science Foundation [31000611, 91019020, 31171397]
- Specialized Research Fund for the Doctoral Program of Higher Education [20100171110028]
- Introduced Innovative R&D Team of Guangdong Province [201001Y0104687244]
- Zhujiang Program of Science and Technology Nova in Guangzhou [2011J2200082]
- Fundamental Research Funds for the Central Universities [11lgpy22, 11lgjc08]
- National Cancer Institute (NCI) [CA133249]
- National Institute of General Medical Sciences (NIGMS) [GM095599]
- Welch Foundation [Q-1673]
- GRSA Shared Resource at the Dan L. Duncan Cancer Center [P30CA125123]
- Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (BCM IDDRC) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [5P30HD024064]
The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.
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