Glioblastoma, a highly aggressive form of brain cancer, is notorious for its lethality due to its invasive nature into the surrounding brain tissue and resistance to standard treatments [1]. The resistance of glioblastomas to radiation therapy diminishes treatment efficacy, contributing significantly to the poor prognosis associated with this aggressive brain cancer. Therefore, understanding the mechanisms underpinning glioblastoma’s resistance becomes paramount in the quest for more effective treatment strategies. This challenge motivated our study, aiming to unravel the factors contributing to resistance of glioblastoma cells to radiation therapy and explore potential avenues for overcoming this treatment barrier.

Previous work from our group identified significantly elevated levels of the Holliday Junction Recognition Protein (HJURP) in glioblastoma compared to low-grade gliomas or normal tissues [2-3]. HJURP has emerged as a key player in several cancer types, demonstrating a strong correlation with patient survival [2-11]. Despite this association, the mechanistic bases of HJURP involvement in cancer aggressiveness have remained elusive. Our study uncovers the intricate roles of HJURP, shedding light on its impact on chromatin structure, DNA repair, and potential as a therapeutic target for glioblastoma.

At the molecular level, HJURP orchestrates the loading of the histone H3 variant, CENP-A, at the centromeric chromatin [12-14]. This action epigenetically defines centromeres, which are crucial for proper chromosome segregation. Additionally, HJURP exhibits associations with DNA repair, a facet of its function that has been minimally explored until now. Our research demonstrated that HJURP is recruited to DNA double-strand breaks (DSBs) through a mechanism reliant on chromatin PARylation. Once at the DSB sites, HJURP instigates epigenetic alterations to drive efficient DNA repair. Its presence promotes the turnover of the repressive chromatin components, H3K9me3 and HP1, facilitating DNA damage signaling and aiding in DSB repair especially through the homologous recombination pathway. 

Furthermore, HJURP's influence extends beyond DNA damage response, as its overexpression in glioma cell lines induces a global restructuring of heterochromatin, even in the absence of DNA damage. This not only alters DNA damage signaling but also enhances the radio-resistance of glioma cells. Crucially, our findings indicate that the levels of HJURP expression in tumors correlate with the poor response of patients to radiation therapy. These data position HJURP as a promising target for the development of adjuvant therapies, offering the potential to sensitize tumor cells to irradiation.

In summary, our study expands the understanding of HJURP's multifaceted roles in DNA repair and chromatin dynamics, presenting it as a compelling candidate for future therapeutic interventions aimed at enhancing the efficacy of cancer treatments. Unraveling the intricacies of glioblastoma resistance is not just a scientific pursuit, it is also a crucial step toward advancing in treatment modalities and offering better therapeutic options to those confronting this disease.

References

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