title: Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development.
abstract: 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.
authors.affiliation: Department of Pathology and Cell Biology, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.forename: Wenxia
authors.initials: W
authors.lastname: Jiang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dubois
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Zachary
authors.initials: Z
authors.lastname: Wolner
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000071857:Tumor Suppressor p53-Binding Protein 1; D045567:VDJ Recombinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C498302:Trp53bp1 protein, mouse; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C519508:XLF protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D045567:VDJ Recombinases