Unrepaired DNA Breaks in p53-Deficient Cells Lead to Oncogenic Gene Amplification Subsequent to Translocations

Zhu, Chengming; Mills, Kevin D.; Ferguson, David O.; Lee, Charles; Manis, John P.; Fleming, James C.; Gao, Yuanfeng; Morton, Cynthia C.; Alt, Frederick W.

doi:10.1016/s0092-8674(02)00770-5

Cited by 381 publications

(402 citation statements)

References 58 publications

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“…Images were captured using a LAMBDA LS light source from Sutter Instrument, and a COOL-1300QS camera ASI (ASI, Vista, CA, USA) then analyzed and managed through Case Data Manager Version 5.5 configured by ASI. (Zhu et al, 2002;Bassing et al, 2003;Celeste et al, 2003a;Gladdy et al, 2003;Rooney et al, 2004). Tumor #61 contained a disrupted c-myc locus (Figure 3e) but lacked translocations detectable by spectral karyotyping ( Table 1), suggesting that a genomic deletion involving the 5 0 end of the c-myc locus occurred on one allele.…”

Section: Resultsmentioning

confidence: 95%

“…First, Tp53 induces apoptosis of NHEJdeficient lymphocytes with un-repaired RAG DSBs and inhibits persistence of RAG DSBs outside of G1 phase in NHEJ-sufficient thymocytes Dujka et al, 2010). Second, germline NHEJ/Tp53-deficient mice succumb to pro-B lymphomas with RAG-dependent Igh/c-myc or Igh/N-myc translocations (Difilippantonio et al, 2002;Zhu et al, 2002;Gladdy et al, 2003;Rooney et al, 2004). Third, Tp53 À/À mice expressing a RAG1 mutant that exhibits defects in DNA end joining develop thymic lymphomas with clonal antigen receptor locus translocations (Giblin et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53 À/À ) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multilineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre: Tp53 flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs.Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

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Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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“…4B). It is reported that inactivation of classical NHEJ by knockout of KU70, XRCC4, or Ligase IV leads to elevated frequency of chromosome translocation [20][21][22]. Therefore, we reasoned that ATM cooperates with classical NHEJ factors to suppress occurrence of translocation.…”

Section: Atm Suppresses Dicentric Frequency In the Same Pathway As Dnmentioning

confidence: 96%

Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition orRNAi-mediated knockdown of ATM causes 2~2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

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“…Alteration of both p53 and the KU/DNA-PKcs/XRCC4/Lig4 NHEJ pathway strongly increased genome rearrangements in very complex products (complicons) and tumorigenicity (Ferguson et al, 2000b;Zhu et al, 2002). KU alternative NHEJ pathway(s), which are error-prone and can participate in genome rearrangements (GuirouilhBarbat et al, 2004), should presumably participate.…”

Section: Impact On Genome Stability Maintenancementioning

confidence: 99%

“…Second, GC is generally an error-free repair pathway, but excess or uncontrolled GC can lead to genome instability: GC with one pseudogene can inactivate the functional gene (Amor et al, 1988); GC between two heteroalleles can result in loss of heterozygosity and crossing-over between repeat sequences dispersed through the genome can lead to complex rearrangements such as deletions, amplification, translocation . Third, mice deficient in both NHEJ and p53, develop lymphomas, resulting from rearrangements initiated by V(D)J recombination-activating protein (RAG)-induced DNA cleavage and involving a break-induced replication (BIR) pathway (Vanasse et al, 1999;Difilippantonio et al, 2002;Zhu et al, 2002). BIR is a DSB repair process requiring sequence homology and in part Rad51-dependent in yeast (Kraus et al, 2001;Malkova et al, 2005).…”

Section: Impact On Genome Stability Maintenancementioning

confidence: 99%

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

et al. 2006

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Non-homologous end joining (NHEJ) and homologous recombination (HR) are two pathways that can compete or cooperate for DNA double-strand break (DSB) repair. NHEJ was previously shown to act throughout the cell cycle whereas HR is restricted to late S/G2. Paradoxically, we show here that defect in XRCC4 (NHEJ) leads to over-stimulation of HR when cells were irradiated in G1, not in G2. However, XRCC4 defect did not modify the strict cell cycle regulation for HR (i.e. in S/G2) as attested by (i) the formation of Rad51 foci in late S/G2 whatever the XRCC4 status, and (ii) the fact that neither Rad51 foci nor HR (gene conversion plus single-strand annealing) events induced by ionizing radiation were detected when cells were maintained blocked in G1. Finally, both c-H2AX analysis and pulse field gel electrophoresis showed that following irradiation in G1, some DSBs reached S/G2 in NHEJ-defective cells. Taken together, our results show that when cells are defective in G1/S arrest, DSB produced in G1 and left unrepaired by XRCC4 can be processed by HR but in late S/G2.

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Unrepaired DNA Breaks in p53-Deficient Cells Lead to Oncogenic Gene Amplification Subsequent to Translocations

Cited by 381 publications

References 58 publications

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Mode of ATM-dependent suppression of chromosome translocation

XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells

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