APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination.
Antibody class switch recombination (CSR) occurs by an intrachromosomal deletion requiring generation of double-stranded breaks (DSBs) in switch-region DNA. The initial steps in DSB formation have been elucidated, involving cytosine deamination by activation-induced cytidine deaminase and generation of abasic sites by uracil DNA glycosylase. However, it is not known how abasic sites are converted into single-stranded breaks and, subsequently, DSBs. Apurinic/apyrimidinic endonuclease (APE) efficiently nicks DNA at abasic sites, but it is unknown whether APE participates in CSR. We address the roles of the two major mammalian APEs, APE1 and APE2, in CSR. APE1 deficiency causes embryonic lethality in mice; we therefore examined CSR and DSBs in mice deficient in APE2 and haploinsufficient for APE1. We show that both APE1 and APE2 function in CSR, resulting in the DSBs necessary for CSR and thereby describing a novel in vivo function for APE2.
Guikema
Jeroen E J
JE
Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Linehan
Erin K
EK
Tsuchimoto
Daisuke
D
Nakabeppu
Yusaku
Y
Strauss
Phyllis R
PR
Stavnezer
Janet
J
Schrader
Carol E
CE
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000172:deficiency / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011995:Recombination, Genetic; D013154:Spleen / Q000276:immunology
D005090:Exodeoxyribonucleases; C020133:exodeoxyribonuclease III; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase