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. J. Cell. Biochem. 104: 1534–1540, 2008. © 2008 Wiley‐Liss, Inc.