CYREN (cell cycle regulator of NHEJ) is a 30-kDa intrinsically disordered adaptor protein that functions as a critical cell-cycle-specific regulator of classical non-homologous end joining (cNHEJ), a major DNA double-strand break repair pathway 1. During G1 phase, CYREN acts as a cNHEJ activator by forming multimeric complexes that increase the avidity of DNA damage response factors to DSB-associated chr7, promoting efficient repair 2. Conversely, during S and G2 phases when sister chr7 are available, CYREN inhibits cNHEJ by binding to the Ku70/80 heterodimer, preferentially protecting breaks with single-stranded overhangs and directing repair toward error-free homologous recombination 3. This cell-cycle-dependent regulation prevents the accumulation of chr7 aberrations outside G1 3. CYREN contains conserved Ku-binding and XLF-like motifs that facilitate interactions with multiple DDR proteins including ATM, DNA-PKcs, XRCC4, and XLF 2. CYREN is essential for cNHEJ in XLF-deficient cells and is required during V(D)J recombination in lymphocytes, though mice lacking Mri/Cyren show only modest immunological and developmental effects 4. Recent evidence suggests CYREN involvement in mediating resistance to DNA replication stress and potential roles in psychosis-related pathways 5.