RIF1 is a key regulator of DNA double-strand break (DSB) repair that promotes non-homologous end joining (NHEJ) while suppressing homologous recombination (HR). RIF1 functions by interacting with ATM-phosphorylated TP53BP1 at DSB sites, where it displaces NUDT16L1/TIRR to unmask TP53BP1's tandem Tudor domain and enable DNA recruitment 1. Together with TP53BP1, RIF1 forms the shieldin complex (including SHLD1-3 and REV7) that protects DNA ends from nucleolytic resection 2. This pathway recruits CST-Polα complexes to perform fill-in synthesis, effectively blocking HR and promoting NHEJ repair 3. RIF1 also controls replication timing by delaying helicase activation in specific genomic regions, causing late replication during S phase 4. Through its interaction with protein phosphatase 1 (PP1), RIF1 both stimulates origin licensing by protecting ORC1 from degradation and suppresses origin activation by limiting MCM helicase phosphorylation 5. Super-resolution microscopy reveals that RIF1 and TP53BP1 stabilize three-dimensional chr2 topology at DSB sites, organizing neighboring topologically associating domains into ordered circular arrangements that prevent chr2 decompaction and maintain epigenetic integrity 6. Loss of RIF1 function contributes to PARP inhibitor resistance in BRCA1-deficient cancers 7.