Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.
The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME), and insufficient activation of effector T cells against the tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via the ubiquitin–proteasome system. RNF8 deficiency in the host but sufficiency in implanted melanoma results in immune exclusion and tumor progression due to the upregulation of gal-3. Upregulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cell infiltration in the tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cell infiltration and enhancing immune response in tumors. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for the therapy of “cold” tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.
The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME) and insufficient activation effector T cells to against tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via ubiquitin proteasome system. RNF8 deficiency in host but sufficiency in implanted melanoma results immune exclusion and tumor progression due to up-regulation of gal-3. Up-regulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cells infiltration in tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cells infiltration and enhancing immune response in tumor. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for therapy of “cold” tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.
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