Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development

Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3903-8. doi: 10.1073/pnas.1120160109. Epub 2012 Feb 21.


Nonhomologous end joining (NHEJ), a major pathway of DNA double-strand break (DSB) repair, is required during lymphocyte development to resolve the programmed DSBs generated during Variable, Diverse, and Joining [V(D)J] recombination. XRCC4-like factor (XLF) (also called Cernunnos or NHEJ1) is a unique component of the NHEJ pathway. Although germ-line mutations of other NHEJ factors abrogate lymphocyte development and lead to severe combined immunodeficiency (SCID), XLF mutations cause a progressive lymphocytopenia that is generally less severe than SCID. Accordingly, XLF-deficient murine lymphocytes show no measurable defects in V(D)J recombination. We reported earlier that ATM kinase and its substrate histone H2AX are both essential for V(D)J recombination in XLF-deficient lymphocytes, despite moderate role in V(D)J recombination in WT cells. p53-binding protein 1 (53BP1) is another substrate of ATM. 53BP1 deficiency led to small reduction of peripheral lymphocyte number by compromising both synapse and end-joining at modest level during V(D)J recombination. Here, we report that 53BP1/XLF double deficiency blocks lymphocyte development at early progenitor stages, owing to severe defects in end joining during chromosomal V(D)J recombination. The unrepaired DNA ends are rapidly degraded in 53BP1(-/-)XLF(-/-) cells, as reported for H2AX(-/-)XLF(-/-) cells, revealing an end protection role for 53BP1 reminiscent of H2AX. In contrast to the early embryonic lethality of H2AX(-/-)XLF(-/-) mice, 53BP1(-/-)XLF(-/-) mice are born alive and develop thymic lymphomas with translocations involving the T-cell receptor loci. Together, our findings identify a unique function for 53BP1 in end-joining and tumor suppression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Damage
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation*
  • Lymphocytes / cytology*
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Plasmids / metabolism
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Structure, Tertiary
  • Recombination, Genetic
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor p53-Binding Protein 1
  • VDJ Recombinases / metabolism


  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Trp53bp1 protein, mouse
  • Tumor Suppressor Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • XLF protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • VDJ Recombinases