Role and regulation of human XRCC4-like factor/cernunnos

In mammalian cells, non-homologous end joining (NHEJ) is the major double strand break (DSB) repair mechanism during the G(1) phase of the cell cycle. It also contributes to DSB repair during the S and G(2) 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 by binding of XLF/Cer to the XRCC4-DNA Ligase IV complex, (iii) promotion of the alignment of blunt or other non-complementary DNA ends by XLF/Cer for ligation. XLF/Cer promotes the preservation of 3' overhangs, restricts nucleotide loss and thereby promotes accuracy of DSB joining by XRCC4-DNA Ligase IV during NHEJ and V(D)J recombination.