Identification of a novel gene fusion in ALT positive osteosarcoma
Autor: | Ying Jie Lock, Anqi Dai, Himabindu Gali, Adam Labadorf, Rachel Litman Flynn, Jess Floro, Adeline Matschulat, Matthew Reiss, Emily Mason-Osann |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Heterochromatin Telomeric heterochromatin News Biology telomeres Fusion protein Chromatin remodeling 3. Good health Telomere Cell biology 03 medical and health sciences ATRX 030104 developmental biology Death-associated protein 6 Histone Oncology DAXX biology.protein alternative lengthening of telomeres KIFC3 Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | The Alternative Lengthening of Telomeres (ALT) pathway stimulates telomere elongation and prevents cellular senescence in approximately 60% of osteosarcoma. While the precise mechanism underlying activation of the ALT pathway is unclear, mutations in the chromatin remodeling protein ATRX, histone chaperone DAXX, and the histone variant H3.3 correlate with ALT status. ATRX and DAXX facilitate deposition of the histone variant H3.3 within heterochromatic regions suggesting that loss of ATRX, DAXX, and/or H3.3 lead to defects in the stability of telomeric heterochromatin. Genetic mutations in ATRX, DAXX, and H3.3 have been detected in ALT positive cancers, however, a subset of ALT samples show loss of ATRX or DAXX protein expression or localization without evidence of genetic alterations suggesting additional uncharacterized defects in ATRX/DAXX/H3.3 function. Here, using Next Generation Sequencing we identified a novel gene fusion event between DAXX and the kinesin motor protein, KIFC3, leading to the translation of a chimeric DAXX-KIFC3 fusion protein. Moreover, we demonstrate that the fusion of KIFC3 to DAXX causes defects in DAXX function likely promoting ALT activity. These data highlight a potentially unrecognized mechanism of DAXX inactivation in ALT positive osteosarcoma and provide rationale for thorough and comprehensive analyses of ATRX/DAXX/H3.3 proteins in ALT positive cancers. |
Databáze: | OpenAIRE |
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