Publication Date:
2008-10-22
Description:
Variable, diversity and joining (V(D)J) recombination and class-switch recombination use overlapping but distinct non-homologous end joining pathways to repair DNA double-strand-break intermediates. 53BP1 is a DNA-damage-response protein that is rapidly recruited to sites of chromosomal double-strand breaks, where it seems to function in a subset of ataxia telangiectasia mutated (ATM) kinase-, H2A histone family member X (H2AX, also known as H2AFX)- and mediator of DNA damage checkpoint 1 (MDC1)-dependent events. A 53BP1-dependent end-joining pathway has been described that is dispensable for V(D)J recombination but essential for class-switch recombination. Here we report a previously unrecognized defect in the joining phase of V(D)J recombination in 53BP1-deficient lymphocytes that is distinct from that found in classical non-homologous-end-joining-, H2ax-, Mdc1- and Atm-deficient mice. Absence of 53BP1 leads to impairment of distal V-DJ joining with extensive degradation of unrepaired coding ends and episomal signal joint reintegration at V(D)J junctions. This results in apoptosis, loss of T-cell receptor alpha locus integrity and lymphopenia. Further impairment of the apoptotic checkpoint causes propagation of lymphocytes that have antigen receptor breaks. These data suggest a more general role for 53BP1 in maintaining genomic stability during long-range joining of DNA breaks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596817/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596817/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Difilippantonio, Simone -- Gapud, Eric -- Wong, Nancy -- Huang, Ching-Yu -- Mahowald, Grace -- Chen, Hua Tang -- Kruhlak, Michael J -- Callen, Elsa -- Livak, Ferenc -- Nussenzweig, Michel C -- Sleckman, Barry P -- Nussenzweig, Andre -- R01AI074953/AI/NIAID NIH HHS/ -- Z01 BC010283-10/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 27;456(7221):529-33. doi: 10.1038/nature07476. Epub 2008 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18931658" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis
;
Chromosomal Proteins, Non-Histone
;
DNA/genetics/*metabolism
;
DNA Breaks
;
DNA-Binding Proteins
;
Gene Rearrangement, T-Lymphocyte/*genetics
;
Genes, T-Cell Receptor alpha/genetics
;
Genomic Instability
;
Intracellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism
;
Lymphopenia/genetics/pathology
;
Mice
;
Models, Genetic
;
Receptors, Antigen, T-Cell/genetics/metabolism
;
*Recombination, Genetic
;
Sequence Homology
;
T-Lymphocytes/cytology/metabolism
;
Thymus Gland/cytology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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