53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

doi:10.1073/pnas.0511259103

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

*Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center, Houston, TX 77030;
^†Center for Blood Research, Children’s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
^¶Joint Program in Transfusion Medicine, Department of Laboratory Medicine, Children’s Hospital, and Department of Pathology, Harvard Medical School, Boston, MA 02115; and
^∥Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Contributed by Frederick W. Alt, December 28, 2005
↵**F.W.A. and P.B.C. contributed equally to this work.

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.

Footnotes

^††To whom correspondence may be addressed. E-mail: alt{at}enders.tch.harvard.edu or phillip.b.carpenter{at}uth.tmc.edu
↵ ^‡Present address: Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, and Department of Cancer Biology, The Leonard and Madlyn Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center, Philadelphia, PA 19104.
↵ ^§Present address: The Jackson Laboratory, Bar Harbor, ME 04609.
Author contributions: J.C.M. and P.B.C. designed research; J.C.M., S.F., M.M.M., C.H.B., K.D.M., M.M.A., J.P.M., N.C.W., G.Z.R., and P.B.C. performed research; J.C.M., S.F., C.H.B., K.D.M., M.M.A., J.P.M., F.W.A., and P.B.C. analyzed data; and P.B.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

DSB,

double-stranded break;

DDR,

DNA damage response;

CSR,

class switch recombination;

SKY,

spectral karyotyping.