The role of Jade-1 in DNA repair in kidney cancer
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Abstract
Renal cell carcinoma (RCC) is one of the ten most common cancers affecting men and women in the United States. Clear-cell RCC is the predominant subtype and is characterized by genomic instability and genetic heterogeneity. The genome is constantly under attack from both endogenous and exogenous stressors. Cells utilize the DNA damage response to signal and correct potentially deleterious alterations to the genome. However, if these processes are unable to adequately repair damaged DNA, serious health issues can arise. Studies in our laboratory have established Jade-1 as a tumor suppressor in renal cancer. Jade-1 induces apoptosis, deters proliferation, and inhibits oncoproteins AKT1 and β-catenin. pVHL, the major renal tumor suppressor, is able to bind and stabilize Jade-1. Furthermore, Jade-1 has known connections to DNA. For example, Jade-1 has transcriptional activity and is associated with the histone acetyltransferases TIP60 and histone acetyltransferase binding to ORC 1 (HBO1). Jade-1 also facilitates DNA replication. However, it is unknown if Jade-1 is directly involved in any DNA repair processes. Through immunoprecipitation studies we discovered that Jade-1 associates with proteins involved in several DNA repair mechanisms, including double-strand break (DSB) repair. Genomic instability, as occurs in RCC, is due to defects in repair of DNA DSBs, making this Jade-1 association particularly relevant to renal cancer. Additional co-immunoprecipitation studies confirmed that Jade-1interacts with DNA-dependent protein kinase catalytic subunit and DNA damage binding protein 1, DNA-PKcs and DDB1. We also demonstrated that Jade-1 protein levels increase when kidney cells are subjected to a radiomimetic agent that induces DSBs. Furthermore, Jade-1 co-localizes to damage sites represented by γH2AX. These foci are undergoing active non-homologous end-joining repair as revealed by phospho-DNA-PKcs signal.
This work provides insight as to how Jade-1, by interacting with DNA damage proteins, functions as a tumor suppressor in RCC. Future investigation could explore how Jade-1 might regulate DNA repair through a host of its known functional activities.
Overall, this work bolsters our understanding of molecular underpinnings of RCC and highlights Jade-1 as a potential therapeutic target.