Multiple functions of MRN in end-joining pathways during isotype class switching.
The Mre11-Rad50-NBS1 (MRN) complex has many roles in response to DNA double-strand breaks, but its functions in repair by nonhomologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in class switch recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end, we have engineered mice that lack the entire MRN complex in B lymphocytes or that possess an intact complex that harbors mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a strong defect in CSR, affecting both the classic and the alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the classical and alternative NHEJ pathways.
Dinkelmann
Maria
M
Department of Pathology, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
Spehalski
Elizabeth
E
Stoneham
Trina
T
Buis
Jeffrey
J
Wu
Yipin
Y
Sekiguchi
JoAnn M
JM
Ferguson
David O
DO
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006657:Histones / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D006657:Histones; D007143:Immunoglobulin Heavy Chains; D047908:Intracellular Signaling Peptides and Proteins; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C508937:MDC1 protein, mouse; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; C576325:Atm protein, mouse; C495198:Rad50 protein, mouse; C475961:gamma-H2AX protein, mouse