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.

A dual role for UVRAG in maintaining chromosomal stability independent of autophagy / Z. Zhao, S. Oh, D. Li, D. Ni, S.D. Pirooz, J. Lee, S. Yang, J. Lee, I. Ghozalli, V. Costanzo, J.M. Stark, C. Liang. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - 22(2012), pp. 1001-1016.

A dual role for UVRAG in maintaining chromosomal stability independent of autophagy

V. Costanzo;
2012

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.
colon-cancer; DNA; protein; centrosome; mechanism; gene; phosphorylation; instability; mutations; induction
Settore MED/04 - Patologia Generale
Article (author)
File in questo prodotto:
File Dimensione Formato  
PIIS1534580712001360.pdf

accesso aperto

Descrizione: Articolo principale
Tipologia: Publisher's version/PDF
Dimensione 2.55 MB
Formato Adobe PDF
2.55 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/732354
Citazioni
  • ???jsp.display-item.citation.pmc??? 49
  • Scopus 73
  • ???jsp.display-item.citation.isi??? 67
social impact