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Maintaining genome integrity is vital for cellular viability and prevention of disease. In this seminar, I will discuss my recent studies that uncover novel mechanisms regulating DNA and RNA damage responses. First, the cold-inducible RNA-binding protein (CIRBP) is identified as a critical factor in DNA double-strand break (DSB) repair. CIRBP is recruited to damaged sites via PARP-1-dependent poly(ADP-ribosyl)ation and facilitates both homologous recombination by promoting the chromatin retention of ATM/MRN complex and downstream signaling. Second, poly(ADP-ribose) polymerase-1 (PARP-1) is shown to mediate the association of the RNA helicase DDX18 with R loops, regulating R-loop homeostasis. Loss of DDX18 leads to R-loop accumulation, replication stress, and genome instability, which can be rescued by RNase H1, underscoring the significance of PARP-1/DDX18 in R-loop regulation and genomic maintenance. Finally, mechanistic insights into 5-fluorouracil (5-FU) action reveal that its cytotoxicity in colorectal cancer (CRC) is primarily driven by RNA damage during ribosome biogenesis, rather than DNA damage. Tumors with high ribosome biogenesis are more susceptible to 5-FU, and enhancing this pathway can potentiate its therapeutic effect. Collectively, these findings highlight emerging roles of RNA-binding proteins and RNA damage responses in genome maintenance and cancer therapy.