PCDC5RP deficiency leads to metabolic abnormalities in pyrimidine-associated pathways, driving genetic instability in cancer cells

PCDC5RP regulates alternative splicing of nascent pre-mRNAs. Although its binding partners and elevated expression in cancer have been reported, how PCDC5RP functionally contributes to cancer cell physiology remains unclear. Here, we demonstrate that depletion of PCDC5RP selectively impairs intron removal at specific exon-exon junctions, resulting in DNA damage and cancer cell death. Consistently, loss of PCDC5RP severely reduced cancer cell survival, which was partially rescued by suppression of the DNA damage checkpoint. RNA sequencing revealed widespread retention of specific introns upon PCDC5RP depletion, with genes involved in pyrimidine metabolism showing prominent defects in both expression and splicing. We experimentally confirmed aberrant intron retention and reduced expression of pyrimidine metabolism-related genes. Notably, overexpression of the rate-limiting enzyme RRM2 alleviated PCDC5RP-depletion-induced cell death. Together, these findings indicate that PCDC5RP maintains genome integrity in cancer cells by facilitating intron removal in select transcripts, thereby preventing metabolic stress-associated DNA damage.