Abstract
The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment—it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 —one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers.
Highlights
The DNA damage response (DDR) consists of various intricate pathways that maintain the integrity of the DNA in our cells, which is continuously threatened by endogenous and exogenous agents [1,2,3]
We found that the absence of BRCA1, which is closely related to the BRCA2 complex and which has E3-ligase activity [45,46,47], did not change degradation of BRCA2 upon hyperthermia (Figure 5D)
We demonstrated that inhibition of the ubiquitin-selective valosin-containing protein (VCP) segregase prevents degradation, and we found ubiquitin enrichment in immunoprecipitates of the BRCA2-complex shortly after hyperthermia induction (Table 1), both of which are indications that BRCA2 degradation might be regulated via ubiquitination
Summary
The DNA damage response (DDR) consists of various intricate pathways that maintain the integrity of the DNA in our cells, which is continuously threatened by endogenous and exogenous agents [1,2,3]. Cancers 2019, 11, 97 sword—by safeguarding the DNA, it prevents accumulation of mutations in genes that might lead to cancer, and counteracts the efficacy of many anti-cancer therapies that are based on the cytotoxicity of DNA damage [4]. It is because of the latter aspect that inhibition of the DDR is of great interest in the context of cancer treatment [5]. The clinical efficacy of PARP-1 inhibitors in turn makes HR an attractive therapeutic target—if one could inhibit HR in a tumor, it would become more sensitive to these treatment modalities
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