title: A dual role for UVRAG in maintaining chromosomal stability independent of autophagy.
abstract: 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Soohwan
authors.initials: S
authors.lastname: Oh
authors.forename: Dapeng
authors.initials: D
authors.lastname: Li
authors.forename: Duojiao
authors.initials: D
authors.lastname: Ni
authors.forename: Sara Dolatshahi
authors.initials: SD
authors.lastname: Pirooz
authors.forename: Joo-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Shunhua
authors.initials: S
authors.lastname: Yang
authors.forename: June-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Irene
authors.initials: I
authors.lastname: Ghozalli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liang
mesh_terms: D000782:Aneuploidy; D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C508298:CEP63 protein, human; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D004247:DNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human