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MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2009 Mar 16; Vol. 206 (3), pp. 669-79. Date of Electronic Publication: 2009 Feb 16. - Publication Year :
- 2009
-
Abstract
- The Mre11-Rad50-Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of antigen receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during lymphocyte antigen receptor gene assembly.
- Subjects :
- Acid Anhydride Hydrolases
Animals
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins antagonists & inhibitors
DNA Repair Enzymes deficiency
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins deficiency
Enzyme Activation
Humans
MRE11 Homologue Protein
Mice
Nuclear Proteins deficiency
Oncogene Proteins v-abl metabolism
Precursor Cells, B-Lymphoid enzymology
Protein Serine-Threonine Kinases antagonists & inhibitors
Recombination, Genetic genetics
Retroviridae
Thymus Gland cytology
Tumor Suppressor Proteins antagonists & inhibitors
VDJ Exons genetics
ATP-Binding Cassette Transporters metabolism
Cell Cycle Proteins metabolism
Chromosomes, Mammalian metabolism
DNA Breaks, Double-Stranded
DNA Repair
DNA Repair Enzymes metabolism
DNA-Binding Proteins metabolism
Homeodomain Proteins metabolism
Nuclear Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 206
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 19221393
- Full Text :
- https://doi.org/10.1084/jem.20081326