53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Julio C. Morales, Sonia Franco, Michael M. Murphy, Craig H. Bassing, Kevin D. Mills, Melissa M. Adams, Nicole C. Walsh, John P. Manis, George Z. Rassidakis, Frederick W. Alt, Phillip B. Carpenter

Research output: Contribution to journalArticle

Abstract

p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair/cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1 -/-) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53-/- mice, 53BP1-/-/p53-/- animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1-/-/p53 -/-) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53-/- T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1-/-/p53-/- thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.

Original languageEnglish (US)
Pages (from-to)3310-3315
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number9
DOIs
StatePublished - Feb 28 2006

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Genomic Instability
T-Cell Lymphoma
Aneuploidy
T-Lymphocytes
Lymphoma
Immunoglobulin Heavy Chains
Double-Stranded DNA Breaks
Teratoma
Cell Cycle Checkpoints
Ionizing Radiation
Cytogenetics
DNA Repair
Sarcoma
Histones
Genetic Recombination
Cell Cycle
Carrier Proteins
Neoplasms

Keywords

  • Aneuploidy
  • Thymic lymphoma
  • Translocations

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Morales, J. C., Franco, S., Murphy, M. M., Bassing, C. H., Mills, K. D., Adams, M. M., ... Carpenter, P. B. (2006). 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proceedings of the National Academy of Sciences of the United States of America, 103(9), 3310-3315. https://doi.org/10.1073/pnas.0511259103

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. / Morales, Julio C.; Franco, Sonia; Murphy, Michael M.; Bassing, Craig H.; Mills, Kevin D.; Adams, Melissa M.; Walsh, Nicole C.; Manis, John P.; Rassidakis, George Z.; Alt, Frederick W.; Carpenter, Phillip B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 9, 28.02.2006, p. 3310-3315.

Research output: Contribution to journalArticle

Morales, JC, Franco, S, Murphy, MM, Bassing, CH, Mills, KD, Adams, MM, Walsh, NC, Manis, JP, Rassidakis, GZ, Alt, FW & Carpenter, PB 2006, '53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 9, pp. 3310-3315. https://doi.org/10.1073/pnas.0511259103
Morales, Julio C. ; Franco, Sonia ; Murphy, Michael M. ; Bassing, Craig H. ; Mills, Kevin D. ; Adams, Melissa M. ; Walsh, Nicole C. ; Manis, John P. ; Rassidakis, George Z. ; Alt, Frederick W. ; Carpenter, Phillip B. / 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 9. pp. 3310-3315.
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