Details

Autor(en) / Beteiligte

• 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.

Titel

53BP1 and p53 Synergize to Suppress Genomic Instability and Lymphomagenesis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2006-02, Vol.103 (9), p.3310-3315

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.