ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

@article{Calln2007ATMPT,
  title={ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes},
  author={Elsa Call{\'e}n and Mila Jankovic and Simone Difilippantonio and Jeremy A Daniel and Hua Chen and Arkady Celeste and Manuela Pellegrini and Kevin M. McBride and Danny Wangsa and Andrea L Bredemeyer and Barry P. Sleckman and Thomas Ried and Michel C. Nussenzweig and Andr{\'e} Nussenzweig},
  journal={Cell},
  year={2007},
  volume={130},
  pages={63-75}
}
DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and… Expand
ATM and p53 are essential in the cell-cycle containment of DNA breaks during V(D)J recombination in vivo
TLDR
The dynamic multiple functions of ATM are shown in maintaining genomic stability and preventing tumorigenesis in developing lymphocytes, and surprisingly this pathway is not important for containing Rag-2 activity. Expand
MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks
TLDR
It is shown 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 D SBs. Expand
Breaking down cell cycle checkpoints and DNA repair during antigen receptor gene assembly
TLDR
This review discusses how two complementary genome maintenance functions mediated by ATM prevent lymphocytes from adapting to persistent DNA damage. Expand
Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes
TLDR
It is indicated that ATM deficiency leads to formation of chromosome 12 dicentrics via recombination-activating gene-initiated IgH DSBs in progenitor B cells and that these dicentric can be propagated developmentally into mature B cells where they generate new DSBS downstream of IgH via breakage-fusion-bridge cycles. Expand
Concurrent V(D)J recombination and DNA end instability increase interchromosomal trans-rearrangements in ATM-deficient thymocytes
TLDR
TCR trans-rearrangements are not the result of trans-synaptic complex formation, but they are instead because of unstable cis synaptic complexes that form simultaneously at distinct TCR loci, indicating that ATM function extends beyond timely resolution of DNA breaks. Expand
The Role for the DSB Response Pathway in Regulating Chromosome Translocations.
In response to DNA double strand breaks (DSB), mammalian cells activate the DNA Damage Response (DDR), a network of factors that coordinate their detection, signaling and repair. Central to thisExpand
Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks.
TLDR
The current understanding of C-NHEJ and A-EJ in the context of V(D)J recombination, CSR, and the formation of chromosomal translocations is discussed. Expand
Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis
TLDR
An approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient lymphocytes. Expand
Breaks invisible to the DNA damage response machinery accumulate in ATM‐deficient cells
TLDR
The present results suggest that a significant subset of the AT long‐lived DSBs may persist as “invisible” D SBs due to deficient detection by the DNA damage repair machinery. Expand
The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage
TLDR
It is shown that a defect in feedback control of RAG2 activity gives rise to bi-locus breaks and damage on Tcra/d and Igh in the same T cell at the same developmental stage, which provides a direct mechanism for generating these inter- locus rearrangements. Expand
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ATM stabilizes DNA double-strand-break complexes during V(D)J recombination
TLDR
It is shown that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly, providing a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia. Expand
Evidence for Replicative Repair of DNA Double-Strand Breaks Leading to Oncogenic Translocation and Gene Amplification
TLDR
Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion, report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Expand
H2AX prevents DNA breaks from progressing to chromosome breaks and translocations.
TLDR
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ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor α locus coding end breaks
TLDR
A unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCRα locus is proposed. Expand
Unrepaired DNA Breaks in p53-Deficient Cells Lead to Oncogenic Gene Amplification Subsequent to Translocations
TLDR
It is shown that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc and IgH sequences, suggesting a general model for oncogenic complicon formation. Expand
ATM regulates ATR chromatin loading in response to DNA double-strand breaks
TLDR
Experimental evidence is provided of an active cross talk between ATM and ATR signaling pathways in response to DNA damage, which places ATM activity upstream of ATR recruitment to IR-damaged chromatin. Expand
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TLDR
Routine surveillance of intermediates in V(D)J recombination by ATM helps suppress potentially oncogenic translocations when repair fails, and it is suggested that ATM phosphorylates target proteins in situ. Expand
Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes
TLDR
It is demonstrated that ATM deficiency leads to broad defects in coding joint formation in developing B and T lymphocytes in vivo, and a potential molecular explanation as to why the developmental impact of these defects could be more pronounced in the T cell compartment is provided. Expand
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
TLDR
It is shown that ATM and the nuclease activity of meiotic recombination 11 are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Expand
Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation
TLDR
An isogenic set of stable cell lines differing only in their ATM status from the chicken B cell line DT40 by targeted integration provides a useful model system for analysing p53-independent ATM functions. Expand
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