Homologous recombination is necessary for normal lymphocyte development.
Primary immunodeficiencies are rare but serious diseases with diverse genetic causes. Accumulating evidence suggests that defects in DNA double-strand break (DSB) repair can underlie many of these syndromes. In this context, the nonhomologous end joining pathway of DSB repair is absolutely required for lymphoid development, but possible roles for the homologous recombination (HR) pathway have remained more controversial. While recent evidence suggests that HR may indeed be important to suppress lymphoid transformation, the specific relationship of HR to normal lymphocyte development remains unclear. We have investigated roles of the X-ray cross-complementing 2 (Xrcc2) HR gene in lymphocyte development. We show that HR is critical for normal B-cell development, with Xrcc2 nullizygosity leading to p53-dependent early S-phase arrest. In the absence of p53 (encoded by Trp53), Xrcc2-null B cells can fully develop but show high rates of chromosome and chromatid fragmentation. We present a molecular model wherein Xrcc2 is important to preserve or restore replication forks during rapid clonal expansion of developing lymphocytes. Our findings demonstrate a key role for HR in lymphoid development and suggest that Xrcc2 defects could underlie some human primary immunodeficiencies.
Caddle
Lura B
LB
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Hasham
Muneer G
MG
Schott
William H
WH
Shirley
Bobbi-Jo
BJ
Mills
Kevin D
KD
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002478:Cells, Cultured / Q000166:cytology; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D018920:Coculture Techniques; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D017353:Gene Deletion; D016158:Genes, p53; D007075:Immunoglobulin M / Q000096:biosynthesis; D015851:Interleukin-7 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000196:embryology; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells / Q000378:metabolism; D011995:Recombination, Genetic; D016196:S Phase; D012689:Sequence Homology, Nucleic Acid; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D015851:Interleukin-7; D016159:Tumor Suppressor Protein p53; C491866:Xrcc2 protein, mouse; D017493:Leukocyte Common Antigens