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PMID: 16492765 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·2006-02-28 ·Pages 3310-5

Morales JC, Franco S, Murphy MM, Bassing CH, Mills KD, Adams MM, Walsh NC, Manis JP, Rassidakis GZ, Alt FW, Carpenter PB

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.

MeSH Terms
Animals Cell Transformation, Neoplastic/genetics,metabolism,pathology Cells, Cultured Chromosomal Proteins, Non-Histone Chromosomes, Mammalian/genetics Cytosol/metabolism DNA-Binding Proteins Genomic Instability/genetics Intracellular Signaling Peptides and Proteins/deficiency,genetics,metabolism Lymphoma/genetics,metabolism,pathology Mice Mice, Knockout Mutation/genetics Phosphoproteins/deficiency,genetics,metabolism Survival Rate Thymus Neoplasms/genetics,metabolism,pathology Tumor Suppressor Protein p53/deficiency,genetics,metabolism Tumor Suppressor p53-Binding Protein 1
Chemicals
Chromosomal Proteins, Non-Histone DNA-Binding Proteins Intracellular Signaling Peptides and Proteins Phosphoproteins Trp53bp1 protein, mouse Tumor Suppressor Protein p53 Tumor Suppressor p53-Binding Protein 1
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Morales Julio C
Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center, Houston, 77030, USA.
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
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0511259103
Published
2006-02-28
Epub
2006-00-21
Pages
3310-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1413919
Subset
IM
Grants
NCI NIH HHS · P01 CA109901 · United States
NIGMS NIH HHS · GM65812 · United States
NCI NIH HHS · P01 CA092625 · United States
NIGMS NIH HHS · R56 GM065812 · United States
NCI NIH HHS · CA92625 · United States
NIGMS NIH HHS · R01 GM065812 · United States
NCI NIH HHS · CA109901 · United States
External Links
PubMed source DOI: 10.1073/pnas.0511259103 PMC Full Text View journal details
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