A Dual Role for UVRAG in Maintaining Chromosomal Stability Independent of Autophagy

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• 作者：Zhen Zhao¹ ; ⁴ ; Soohwan Oh¹ ; ⁴ ; Dapeng Li¹ ; Duojiao Ni¹ ; Sara  ; Dolatshahi Pirooz¹ ; Joo-Hyung Lee¹ ; Shunhua Yang¹ ; June-Yong Lee¹ ; Irene Ghozalli¹ ; Vincenzo Costanzo² ; Jeremy  ; M. Stark³ ; Chengyu Liang¹ ; ^{chengyu.liang@usc.edu}
• 刊名：Developmental Cell
• 出版年：2012
• 期刊代码：10_15345807
• 类别：bio
• 出版时间：15 May, 2012
• 卷：22
• 期：5
• 页码：1001-1016
• 文件大小：2552 K

摘要

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Summary

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聽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聽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.