Biology:Non-homologous end-joining factor 1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Non-homologous end-joining factor 1 (NHEJ1), also known as Cernunnos or XRCC4-like factor (XLF), is a protein that in humans is encoded by the NHEJ1 gene.[1] XLF was originally discovered as the protein mutated in five patients with growth retardation, microcephaly, and immunodeficiency.[2] The protein is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Patients with XLF mutations also have immunodeficiency due to a defect in V(D)J recombination, which uses NHEJ to generate diversity in the antibody repertoire of the immune system. XLF interacts with DNA ligase IV and XRCC4 and is thought to be involved in the end-bridging or ligation steps of NHEJ. The yeast (Saccharomyces cerevisiae) homolog of XLF is Nej1.[3]

Phenotypes

In contrast to the profound immunodeficiency phenotype of XLF deletion in humans, deletion of XLF alone has a mild phenotype in mice.[4] However, combining a deletion of XLF with deletion of the ATM kinase causes a synthetic defect in NHEJ, suggesting partial redundancy in the function of these two proteins in mice.[5]

Structure

XLF is structurally similar to XRCC4, existing as a constitutive dimer with an N-terminal globular head domain, an alpha-helical stalk, and an unstructured C-terminal region (CTR).[6]

Interactions

XLF has been shown to interact with XRCC4,[7] and with Ku protein,[8] and it can also interact weakly with DNA.[9][10] Co-crystal structures of XLF and XRCC4 suggest that the two proteins can form hetero-oligomers via head-to-head interaction of alternating XLF and XRCC4 subunits.[11][12][13] These XRCC4-XLF filaments have been proposed to bridge DNA prior to end ligation during NHEJ. Formation of XRCC4-XLF oligomers can be disrupted by interaction of the C-terminal domain of XRCC4 with the BRCT domain of DNA ligase IV.[11]

Hematopoietic stem cell aging

Deficiency of NHEJ1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time.[14] Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors.[15] These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation.[15]

References

  1. ↑ "Entrez Gene: NHEJ1 nonhomologous end-joining factor 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79840. 
  2. ↑ "Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly". Cell 124 (2): 287–99. Jan 2006. doi:10.1016/j.cell.2005.12.030. PMID 16439204. 
  3. ↑ "Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1". The Journal of Biological Chemistry 281 (20): 13857–60. May 2006. doi:10.1074/jbc.C500473200. PMID 16571728. 
  4. ↑ "Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination". Molecular Cell 31 (5): 631–40. Sep 2008. doi:10.1016/j.molcel.2008.07.017. PMID 18775323. 
  5. ↑ "ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks". Nature 469 (7329): 250–4. Jan 2011. doi:10.1038/nature09604. PMID 21160472. Bibcode: 2011Natur.469..250Z. 
  6. ↑ "Crystal structure of human XLF: a twist in nonhomologous DNA end-joining". Molecular Cell 28 (6): 1093–101. Dec 2007. doi:10.1016/j.molcel.2007.10.024. PMID 18158905. 
  7. ↑ "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair 6 (10): 1507–16. Oct 2007. doi:10.1016/j.dnarep.2007.04.014. PMID 17567543. 
  8. ↑ "Ku recruits XLF to DNA double-strand breaks". EMBO Reports 9 (1): 91–6. Jan 2008. doi:10.1038/sj.embor.7401137. PMID 18064046. 
  9. ↑ "Cooperative assembly of a protein-DNA filament for nonhomologous end joining". The Journal of Biological Chemistry 288 (25): 18110–20. Jun 2013. doi:10.1074/jbc.M113.464115. PMID 23620595. 
  10. ↑ "Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity". The Journal of Biological Chemistry 282 (15): 11155–62. Apr 2007. doi:10.1074/jbc.M609904200. PMID 17317666. 
  11. ↑ 11.0 11.1 "A human XRCC4-XLF complex bridges DNA". Nucleic Acids Research 40 (4): 1868–78. Feb 2012. doi:10.1093/nar/gks022. PMID 22287571. 
  12. ↑ "Non-homologous end-joining partners in a helical dance: structural studies of XLF-XRCC4 interactions". Biochemical Society Transactions 39 (5): 1387–92, suppl 2 p following 1392. Oct 2011. doi:10.1042/BST0391387. PMID 21936820. 
  13. ↑ "Structural characterization of filaments formed by human Xrcc4-Cernunnos/XLF complex involved in nonhomologous DNA end-joining". Proceedings of the National Academy of Sciences of the United States of America 108 (31): 12663–8. Aug 2011. doi:10.1073/pnas.1100758108. PMID 21768349. Bibcode: 2011PNAS..10812663R. 
  14. ↑ "Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency". Blood 124 (10): 1622–5. 2014. doi:10.1182/blood-2014-05-574863. PMID 25075129. 
  15. ↑ 15.0 15.1 "Brief report: a human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors". Stem Cells 31 (9): 2015–23. 2013. doi:10.1002/stem.1456. PMID 23818183. 

Further reading



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