DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway - PubMed (original) (raw)
DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway
K M Frank et al. Mol Cell. 2000 Jun.
Free article
Abstract
DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryonic lethality, massive neuronal apoptosis, arrested lymphogenesis, and various cellular defects. Herein, we assess potential roles in this phenotype for INK4a/ARF and p53, two proteins implicated in apoptosis and senescence. INK4a/ARF deficiency rescued proliferation/senescence defects of Lig4-deficient fibroblasts but not other phenotypic aspects. In contrast, p53 deficiency rescued embryonic lethality, neuronal apoptosis, and fibroblast proliferation/senescence defects but not lymphocyte development or radiosensitivity. Young Lig4/p53 double null mice routinely died from pro-B lymphomas. Thus, in the context of Lig4 deficiency, embryonic lethality and neuronal apoptosis likely result from a p53-dependent response to unrepaired DNA damage, and neuronal apoptosis and lymphocyte developmental defects can be mechanistically dissociated.
Similar articles
- Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.
Sekiguchi J, Ferguson DO, Chen HT, Yang EM, Earle J, Frank K, Whitlow S, Gu Y, Xu Y, Nussenzweig A, Alt FW. Sekiguchi J, et al. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3243-8. doi: 10.1073/pnas.051632098. Epub 2001 Mar 6. Proc Natl Acad Sci U S A. 2001. PMID: 11248063 Free PMC article. - The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining.
Park J, Welner RS, Chan MY, Troppito L, Staber PB, Tenen DG, Yan CT. Park J, et al. J Immunol. 2016 Jan 1;196(1):244-55. doi: 10.4049/jimmunol.1403099. Epub 2015 Nov 25. J Immunol. 2016. PMID: 26608917 Free PMC article. - A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis.
Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J, Bronson RT, Malynn BA, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin SH, Greenberg ME, Alt FW. Gao Y, et al. Cell. 1998 Dec 23;95(7):891-902. doi: 10.1016/s0092-8674(00)81714-6. Cell. 1998. PMID: 9875844 - Ligase IV syndrome.
Chistiakov DA. Chistiakov DA. Adv Exp Med Biol. 2010;685:175-85. doi: 10.1007/978-1-4419-6448-9_16. Adv Exp Med Biol. 2010. PMID: 20687505 Review. - Ligase IV syndrome.
Chistiakov DA, Voronova NV, Chistiakov AP. Chistiakov DA, et al. Eur J Med Genet. 2009 Nov-Dec;52(6):373-8. doi: 10.1016/j.ejmg.2009.05.009. Epub 2009 May 23. Eur J Med Genet. 2009. PMID: 19467349 Review.
Cited by
- A human iPSC model of Ligase IV deficiency reveals an important role for NHEJ-mediated-DSB repair in the survival and genomic stability of induced pluripotent stem cells and emerging haematopoietic progenitors.
Tilgner K, Neganova I, Moreno-Gimeno I, Al-Aama JY, Burks D, Yung S, Singhapol C, Saretzki G, Evans J, Gorbunova V, Gennery A, Przyborski S, Stojkovic M, Armstrong L, Jeggo P, Lako M. Tilgner K, et al. Cell Death Differ. 2013 Aug;20(8):1089-100. doi: 10.1038/cdd.2013.44. Epub 2013 May 31. Cell Death Differ. 2013. PMID: 23722522 Free PMC article. - Effects of expression level of DNA repair-related genes involved in the NHEJ pathway on radiation-induced cognitive impairment.
Zhang LY, Chen LS, Sun R, Ji SJ, Ding YY, Wu J, Tian Y. Zhang LY, et al. J Radiat Res. 2013 Mar 1;54(2):235-42. doi: 10.1093/jrr/rrs095. Epub 2012 Nov 7. J Radiat Res. 2013. PMID: 23135157 Free PMC article. - Effect of maternal Tp53 gene G412C polymorphism on neural tube defects: A study from North India.
Arora J, Saraswathy KN, Deb R. Arora J, et al. Indian J Hum Genet. 2012 May;18(2):177-82. doi: 10.4103/0971-6866.100757. Indian J Hum Genet. 2012. PMID: 23162292 Free PMC article. - Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
Difilippantonio MJ, Petersen S, Chen HT, Johnson R, Jasin M, Kanaar R, Ried T, Nussenzweig A. Difilippantonio MJ, et al. J Exp Med. 2002 Aug 19;196(4):469-80. doi: 10.1084/jem.20020851. J Exp Med. 2002. PMID: 12186839 Free PMC article. - The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis.
Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, Sexl V, Snyder L, Rehg J, Ihle JN. Piekorz RP, et al. EMBO J. 2002 Feb 15;21(4):653-64. doi: 10.1093/emboj/21.4.653. EMBO J. 2002. PMID: 11847113 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous