期刊
DEVELOPMENTAL CELL
卷 22, 期 5, 页码 1001-1016出版社
CELL PRESS
DOI: 10.1016/j.devcel.2011.12.027
关键词
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资金
- National Institutes of Health (NIH) [E14TG2a.4, AC0571, R01 CA140964, R21 AI083841, R01 CA120954]
- National Cancer Institute Cancer Center [5 P30 CA014089]
- USC
- Baxter Foundation
- American Cancer Society [RSG-11-121-01-CCG]
- National Institute of Allergy and Infectious Diseases [NIAID U19AI083025]
- Norris Cancer Center [P30CA014089-34]
Autophagy defects have recently been associated with chromosomal instability, a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-break repair by directly binding and activating DNA-PK in nonhomologous end joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was also found to be localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity.
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