Cullin 5 is a novel candidate tumor suppressor in renal cell carcinoma involved in the maintenance of genome stability

Abstract

Clear cell renal cell carcinoma (ccRCC) is intimately associated with defects in ubiquitin-mediated protein degradation. Herein, we report that deficiency in the E3 ligase subunit cullin 5 (CUL5) promotes chromosomal instability and is an independent negative prognostic factor in ccRCC. CUL5 was initially identified in an RNA interference screen as a novel regulator of centrosome duplication control. We found that depletion of CUL5 rapidly promotes centriole overduplication and mitotic errors. Downregulation of CUL5 also caused an increase of DNA damage that was found to involve impaired DNA double-strand break repair. Using immunohistochemistry, CUL5 protein expression was found to be below detection level in the majority of RCCs. A re-analysis of the TCGA ccRCC cohort showed that a reduced CUL5 gene expression or CUL5 deletion were associated with a significantly worse overall patient survival. In conclusion, our results indicate that CUL5 functions as a novel tumor suppressor with prognostic relevance in ccRCC and is critically involved in the maintenance of genome stability.

Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

“… 18 , 19 11p15.5 deletion 73 CUL5 CUL5, NPAT, DLAT, RDX, AASDHPPT 11q22.3 Refs. 18 , 19 CUL5 74 COG6 COG6, COG3, AKAP11, ELF1, FNDC3A, GPALPP1, VPS36, ZC3H13, UTP14C 13q14.3 Ref. 18 Co-deleted with RB1 75 TRIP11 TRIP11, GOLGA5, BTBD7, ATG2B, PAPOLA, DICER1, PPP4R3A 14q32.12 Ref.…”

Shared loci of telomere length with brain morphology, and pleiotropy in transcriptomic and epigenomic profiles of brain

“…JPH4 belongs to the junctophilin family, is primarily expressed in neurons and regulates calcium signaling in normal brain development (Landstrom et al, 2014). CUL5 (cullin5) encodes the vasopressin-activated calcium-mobilizing receptor (VACM-1) and is responsible for chromosomal stability and DNA repair mechanisms (Tapia-Laliena et al, 2019). Neural stem cells are precursors of neurons and glial cells in the brain and periodic responses from calcium signaling drive cell-specific neurogenesis (Toth et al, 2016).…”

A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

“…While human endothelial cells are growing, thalidomide, a medication that limits cell proliferation by limiting angiogenesis, has been shown to decrease the quantity of Cul5 present in the nuclei of the cells. Using anti-Cul siRNA, we could reduce the antiproliferative effects of thalidomide in both human endothelial cells and rat endothelial cells that had been genetically modified to lack Cul5 …”