GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310281/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310281GEOGSEfalseRPL22L1-dependent translational control of DNA repair confers chemoresistanceRibosome heterogeneity has emerged as a regulatory layer in gene expression, yet its biological roles in cancers remain poorly understood. Here, we identify RPL22L1, a paralog of the ribosomal protein RPL22, as a key modulator of DNA damage response (DDR) in colorectal cancer cells. DNA damage induces RPL22L1 upregulation and ribosomal incorporation, forming RPL22L1-containing ribosomes. Ribosome profiling revealed that RPL22L1-containing ribosomes preferentially translate mRNAs with highly structured 5’ untranslated region (5’UTR). In particular, RPL22L1 enhances the translation of ATRX through an internal ribosome entry site (IRES)-dependent mechanism. ATRX subsequently recruits DNA-PKcs to DNA damage sites, thereby enhancing the non-homologous end joining (NHEJ) activity. RPL22L1 loss creates exploitable DDR vulnerabilities, sensitizing cancer cells to cisplatin and PARP inhibitors in vitro and in vivo. Collectively, these findings uncover a specialized ribosome-mediated translational program in DDR and highlight RPL22L1 as a potential therapeutic target in DNA damage-based cancer therapy.2026/06/21GSE310281GSM9293331GSM9293330GSM9293326GSM9293328GSM9293327GSM929332924676310281Homo sapiens