Role and regulation of human XRCC4‐like factor/cernunnos

AbstractIn mammalian cells, non‐homologous end joining (NHEJ) is the major double strand break (DSB) repair mechanism during the G1 phase of the cell cycle. It also contributes to DSB repair during the S and G2 phases. Ku heterodimer, DNA PKcs, XRCC4 and DNA Ligase IV constitute the core NHEJ machinery, which joins directly ligatable ends. XRCC4‐like factor/Cernunnos (XLF/Cer) is a recently discovered interaction partner of XRCC4. Current evidence suggests the following model for the role of XLF/Cer in NHEJ: after DSB induction, the XRCC4‐DNA Ligase IV complex promotes efficient accumulation of XLF/Cer at DNA damage sites via constitutive interaction of the XRCC4 and XLF/Cer head domains and dependent on components of the DNA PK complex. Ku alone can stabilise the association of XLF/Cer with DNA ends. XLF/Cer stimulates ligation of complementary and non‐complementary DNA ends by XRCC4‐DNA Ligase IV. This activity involves the carboxy‐terminal DNA binding region of XLF/Cer and could occur via different, non‐exclusive modes: (i) enhancement of the stability of the XRCC4‐DNA Ligase IV complex on DNA ends by XLF/Cer, (ii) modulation of the efficiency and/or specificity of DNA Ligase IV