Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome

Nijnik, Anastasia, Dawson, Sara, Woodbine, Lisa, Visetnoi, Supawan, Bennett, Sophia, Jones, Margaret, Turner, Gareth D, Jeggo, Penelope A, Goodnow, Christopher C and Cornall, Richard J (2009) Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. Journal of Clinical Investigation, 119 (6). pp. 1696-1705. ISSN 00219738

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Abstract

Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radiosensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway. Lig4-null mice are embryonic lethal, and better mouse models are needed to study human LigIV syndrome. We recently identified a viable mouse strain with a Y288C hypomorphic mutation in the Lig4 gene. Lig4Y288C mice exhibit a greater than 10-fold reduction of LigIV activity in vivo and recapitulate the immunodeficiency and growth retardation seen in human patients. Here, we have demonstrated that the Lig4Y288C mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination. We also highlight a high incidence of thymic tumors in the Lig4Y288C mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome.

Item Type: Article
Keywords: SEVERE COMBINED IMMUNODEFICIENCY; STRAND BREAK REPAIR; DEFICIENT B-CELLS; V(D)J RECOMBINATION; EMBRYONIC LETHALITY; TUMOR-SUPPRESSOR; LIG4 SYNDROME; MICE; MUTATIONS; KU70
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Gee Wheatley
Date Deposited: 21 Dec 2009
Last Modified: 07 Mar 2017 07:16
URI: http://sro.sussex.ac.uk/id/eprint/2267

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