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

Abstract

SUMMARY Autophagy defects have been recently associated with chromosomal instability (CIN), 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-breaks repair by directly binding and activating DNA-PK in non-homologous end-joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was found also 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.

Role of Aldose Reductase in the Metabolism and Detoxification of Carnosine-Acrolein Conjugates

“…(Table 4). A similar adduct was detected with a histidine residue of UV radiation resistance gene, a known regulator of autophagy (48,49) and collagen ␣-1(IV) chain (Table 4). Similarly, dipropanal-␤-Ala-His conjugates (m/z 339) were also found to form dehydrated adducts with the histidine residue of phosphatidylinositol kinase type 3␣ and the cysteine residue of UPF0378 proteins.…”

Retrograde signaling from autophagy modulates stress responses

“…As part of a complex with Beclin 1 and Vps34, this broadly multifunctional protein (Table 1) behaves as a type 3 PI3K and contributes to the stimulation of autophagy. In the nuclei of irradiated cells, UVRAG is bound to DNA-dependent protein kinase, a key enzyme involved in recognizing sites of DNA damage and in NHEJ (106). Furthermore, UVRAG also participates in centrosome protection because depletion of UVRAG leads to centrosome amplification with consequent malfunctioning of the spindle apparatus and errors in chromosome segregation.…”

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways

“…UVRAG, the other target of miR-33a, has been reported as regulating autophagy (27) and chromosome stability (28,29) and acting as a tumor suppressor because allelic mutation of UVRAG was found at high frequencies in human colon cancers and its ectopic expression in a colon cancer cell line resulted in decreased proliferation and xenograft tumor formation (30). We did not detect any alteration in the ratio of LC3 I/II in GICs or non-GICs where the level of miR-33a was manipulated (data not shown), indicating that miR-33a would not affect autophagy in the glioma cells.…”