Non-homologous end-joining factor 1

Nonhomologous end-joining factor 1

Rendering based on PDB 2QM4​.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NHEJ1 ; XLF
External IDs OMIM: 611290 MGI: 1922820 HomoloGene: 11714 GeneCards: NHEJ1 Gene
Orthologs
Species Human Mouse
Entrez 79840 75570
Ensembl ENSG00000187736 ENSMUSG00000026162
UniProt Q9H9Q4 Q3KNJ2
RefSeq (mRNA) NM_024782 NM_029342
RefSeq (protein) NP_079058 NP_083618
Location (UCSC) Chr 2:
219.08 – 219.16 Mb		 Chr 1:
74.97 – 75.05 Mb
PubMed search

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".
  2. ↑ Buck D, Malivert L, de Chasseval R, Barraud A, Fondanèche MC, Sanal O, Plebani A, Stéphan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P (Jan 2006). "Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly". Cell 124 (2): 287–99. doi:10.1016/j.cell.2005.12.030. PMID 16439204.
  3. ↑ Callebaut I, Malivert L, Fischer A, Mornon JP, Revy P, de Villartay JP (May 2006). "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. doi:10.1074/jbc.C500473200. PMID 16571728.
  4. ↑ Li G, Alt FW, Cheng HL, Brush JW, Goff PH, Murphy MM, Franco S, Zhang Y, Zha S (Sep 2008). "Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination". Molecular Cell 31 (5): 631–40. doi:10.1016/j.molcel.2008.07.017. PMC 2630261. PMID 18775323.
  5. ↑ Zha S, Guo C, Boboila C, Oksenych V, Cheng HL, Zhang Y, Wesemann DR, Yuen G, Patel H, Goff PH, Dubois RL, Alt FW (Jan 2011). "ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks". Nature 469 (7329): 250–4. doi:10.1038/nature09604. PMC 3058373. PMID 21160472.
  6. ↑ Andres SN, Modesti M, Tsai CJ, Chu G, Junop MS (Dec 2007). "Crystal structure of human XLF: a twist in nonhomologous DNA end-joining". Molecular Cell 28 (6): 1093–101. doi:10.1016/j.molcel.2007.10.024. PMID 18158905.
  7. ↑ Deshpande RA, Wilson TE (Oct 2007). "Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4". DNA Repair 6 (10): 1507–16. doi:10.1016/j.dnarep.2007.04.014. PMC 2064958. PMID 17567543.
  8. ↑ Yano K, Morotomi-Yano K, Wang SY, Uematsu N, Lee KJ, Asaithamby A, Weterings E, Chen DJ (Jan 2008). "Ku recruits XLF to DNA double-strand breaks". EMBO Reports 9 (1): 91–6. doi:10.1038/sj.embor.7401137. PMC 2246615. PMID 18064046.
  9. ↑ Tsai CJ, Chu G (Jun 2013). "Cooperative assembly of a protein-DNA filament for nonhomologous end joining". The Journal of Biological Chemistry 288 (25): 18110–20. doi:10.1074/jbc.M113.464115. PMID 23620595.
  10. ↑ Lu H, Pannicke U, Schwarz K, Lieber MR (Apr 2007). "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. doi:10.1074/jbc.M609904200. PMID 17317666.
  11. 1 2 Andres SN, Vergnes A, Ristic D, Wyman C, Modesti M, Junop M (Feb 2012). "A human XRCC4-XLF complex bridges DNA". Nucleic Acids Research 40 (4): 1868–78. doi:10.1093/nar/gks022. PMC 3287209. PMID 22287571.
  12. ↑ Wu Q, Ochi T, Matak-Vinkovic D, Robinson CV, Chirgadze DY, Blundell TL (Oct 2011). "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. doi:10.1042/BST0391387. PMID 21936820.
  13. ↑ Ropars V, Drevet P, Legrand P, Baconnais S, Amram J, Faure G, Márquez JA, Piétrement O, Guerois R, Callebaut I, Le Cam E, Revy P, de Villartay JP, Charbonnier JB (Aug 2011). "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. doi:10.1073/pnas.1100758108. PMC 3150875. PMID 21768349.
  14. ↑ Avagyan S, Churchill M, Yamamoto K, Crowe JL, Li C, Lee BJ, Zheng T, Mukherjee S, Zha S (2014). "Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency". Blood 124 (10): 1622–5. doi:10.1182/blood-2014-05-574863. PMC 4155271. PMID 25075129.
  15. 1 2 Tilgner K, Neganova I, Singhapol C, Saretzki G, Al-Aama JY, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M (2013). "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. doi:10.1002/stem.1456. PMID 23818183.

Further reading

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