Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge
Department of Molecular Genetics and Microbiology; Program in Immunology and Virology
Animals; B-Lymphocyte Subsets; Cells, Cultured; Coculture Techniques; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Endonucleases; Fluorouracil; Hematopoietic Stem Cells; Lymphocyte Depletion; Lymphocyte Subsets; Lymphopoiesis; Mice; Mice, Knockout; Myelopoiesis; Tumor Suppressor Protein p53
Life Sciences | Medicine and Health Sciences | Women's Studies
B cell development involves rapid cellular proliferation, gene rearrangements, selection, and differentiation, and it provides a powerful model to study DNA repair processes in vivo. Analysis of the contribution of the base excision repair pathway in lymphocyte development has been lacking primarily owing to the essential nature of this repair pathway. However, mice deficient for the base excision repair enzyme, apurinic/apyrimidinic endonuclease 2 (APE2) protein develop relatively normally, but they display defects in lymphopoiesis. In this study, we present an extensive analysis of bone marrow hematopoiesis in mice nullizygous for APE2 and find an inhibition of the pro-B to pre-B cell transition. We find that APE2 is not required for V(D)J recombination and that the turnover rate of APE2-deficient progenitor B cells is nearly normal. However, the production rate of pro- and pre-B cells is reduced due to a p53-dependent DNA damage response. FACS-purified progenitors from APE2-deficient mice differentiate normally in response to IL-7 in in vitro stromal cell cocultures, but pro-B cells show defective expansion. Interestingly, APE2-deficient mice show a delay in recovery of B lymphocyte progenitors following bone marrow depletion by 5-fluorouracil, with the pro-B and pre-B cell pools still markedly decreased 2 wk after a single treatment. Our data demonstrate that APE2 has an important role in providing protection from DNA damage during lymphoid development, which is independent from its ubiquitous and essential homolog APE1.
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Citation: J Immunol. 2011 Feb 15;186(4):1943-50. Epub 2011 Jan 12. Link to article on publisher's site
Guikema, Jeroen E. J.; Gerstein, Rachel M.; Linehan, Erin K.; Cloherty, Erin K.; Evan-Browning, Eric; Tsuchimoto, Daisuke; Nakabeppu, Yusaku; and Schrader, Carol E., "Apurinic/apyrimidinic endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge" (2011). Women’s Health Research Faculty Publications. 515.