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NHEJ1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases NHEJ1, XLF, non-homologous end joining factor 1
External IDs OMIM: 611290 MGI: 1922820 HomoloGene: 11714 GeneCards: NHEJ1
Orthologs
SpeciesHumanMouse
Entrez

79840

75570

Ensembl

ENSG00000187736

ENSMUSG00000026162

UniProt

Q9H9Q4

Q3KNJ2

RefSeq (mRNA)

NM_024782

NM_029342

RefSeq (protein)

NP_079058
NP_001364427
NP_001364428

NP_083618

Location (UCSC) Chr 2: 219.08 – 219.16 Mb Chr 1: 75.01 – 75.1 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] XLF was originally discovered as the protein mutated in five patients with growth retardation, microcephaly, and immunodeficiency. [6] 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. [7]

Phenotypes

In contrast to the profound immunodeficiency phenotype of XLF deletion in humans, deletion of XLF alone has a mild phenotype in mice. [8] 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. [9]

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). [10]

Interactions

XLF has been shown to interact with XRCC4, [11] and with Ku protein, [12] and it can also interact weakly with DNA. [13] [14] 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. [15] [16] [17] 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. [15]

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. [18] 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. [19] 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. [19]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000187736 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026162 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: NHEJ1 nonhomologous end-joining factor 1".
  6. ^ 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. S2CID  13075378.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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. Bibcode: 2011Natur.469..250Z. doi: 10.1038/nature09604. PMC  3058373. PMID  21160472.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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. PMC  3689955. PMID  23620595.
  14. ^ 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.
  15. ^ a b 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.
  16. ^ 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. S2CID  8814152.
  17. ^ 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. Bibcode: 2011PNAS..10812663R. doi: 10.1073/pnas.1100758108. PMC  3150875. PMID  21768349.
  18. ^ 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.
  19. ^ a b 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. S2CID  3623309.

Further reading

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