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Replication protein A 70 kDa DNA-binding subunit (RPA1) mRNA encodes the largest subunit of the heterotrimeric RPA complex, which is the primary eukaryotic single-stranded DNA (ssDNA) binding protein. RPA1 is essential for nearly all aspects of DNA metabolism, including DNA replication, various DNA repair pathways such as nucleotide excision repair and homologous recombination, and the coordination of the DNA damage response. In many malignancies, RPA1 is significantly overexpressed to support the high proliferative demands and genomic stability of cancer cells, often correlating with poor clinical outcomes and resistance to DNA-damaging therapies. Targeting RPA1 mRNA using antisense oligonucleotides or RNA interference aims to deplete RPA1 protein levels, thereby inducing replication stress, inhibiting DNA repair, and sensitizing tumor cells to chemotherapy or radiation. While a promising strategy for precision oncology, the fundamental requirement of RPA1 for normal cellular division necessitates careful therapeutic window management to avoid systemic toxicity. Experimental studies have demonstrated that RPA1 knockdown can effectively suppress tumor growth and enhance the efficacy of DNA-damaging agents in various models, including hepatocellular carcinoma and glioblastoma.
Antisense inhibition or RNA interference (RNAi) to induce mRNA degradation, resulting in the depletion of RPA1 protein and subsequent disruption of DNA replication and repair.
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