ZNF460–SNRPB–RDM1 splicing axis promotes clear cell renal cell carcinoma progression through regulation of DNA damage repair

Abstract Small nuclear ribonucleoprotein polypeptide B (SNRPB) is one of the core proteins of the spliceosome. Although its role in spliceosome assembly has been well - established, its carcinogenic potential has just begun to be revealed. We found that its expression is significantly increased in clear cell renal cell carcinoma (ccRCC) and is associated with a poor prognosis. Mechanistically, this study reveals a carcinogenic axis centered around abnormal RNA splicing: the ZNF460–SNRPB–RDM1 axis. The upstream transcription factor ZNF460 directly binds to and activates the SNRPB promoter, leading to the abnormally high expression of the core spliceosome protein SNRPB in ccRCC. Excessive SNRPB interferes with the precise splicing of RDM1 pre - mRNA, resulting in the dysregulated expression of functional RDM1 protein. As a key effector molecule in the homologous recombination repair (HRR) pathway, changes in the expression level of RDM1 alter the sensitivity of ccRCC cells to the PARP inhibitor olaparib. Therefore, this axis is not only a newly discovered driver of ccRCC invasiveness and drug resistance but may also be a new therapeutic target.