Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs.

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Research Abstract Details 

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Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Abstract Text:

V B Holcomb,H Vogel,T Marple,R W Kornegay,P Hasty,

Ku80 maintains the genome by repairing DNA double-strand breaks (DSBs) through nonhomologous end joining (NHEJ), a pathway that repairs nonspecific DSBs and Rag-1 Rag-2 (Rag)-specific DSBs. As a result, Ku80 deletion results in phenotypes characteristic of defective repair for both nonspecific DSBs (gamma-radiation hypersensitivity and genomic instability) and Rag-specific DSBs (immunodeficiency). ku80(-/-) mice also exhibit neuronal apoptosis, but we do not know the type of DSBs responsible for this response. In spite of genomic instability and immunodeficiency, cancer incidence is not increased in ku80(-/-) mice. However, deletion of the tumor suppressor, p53 greatly increases pro-B-cell lymphoma in ku80(-/-) mice due to IgH/c-Myc translocations suggesting that responses to Rag-specific DNA DSBs suppress cancer. Like suppression of pro-B-cell lymphoma, neuronal apoptosis requires p53 presenting the intriguing possibility that Rag-specific DSBs mediate neuronal development as they do lymphocyte development. Here we delete Rag-1 from ku80(-/-)p53(-/-) mice to differentiate the impact nonspecific vs Rag-specific DSBs have on ku80(-/-) mice. We find that deleting Rag-1 prevents pro-B cell lymphoma confirming Rag-induced DSBs induce this form of cancer. Both the triple mutant mice and the p53(-/-)rag-1(-/-) mice exhibit T-cell lymphoma and medulloblastoma; incidence of T-cell lymphoma is the same for both cohorts whereas incidence of medulloblastoma is higher for the triple-mutant cohort. Thus, p53-mediated neuronal apoptosis likely suppresses medulloblastoma in Ku80-deleted mice and Ku80 likely suppresses medulloblastoma by repairing nonspecific DNA DSBs instead of Rag-specific DSBs. Our observations are the first to show that Ku80 suppresses cancer caused by nonspecific DNA damage and we present a novel mouse model for medulloblastoma.

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Publishing Authors By Initials

VB Holcomb,H Vogel,T Marple,RW Kornegay,P Hasty,

For similar proteins: dna-binding proteins: tumor suppressor protein p53 research abstracts see: proteins: dna-binding proteins: tumor suppressor protein p53 research

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Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Oncogene

VOLUME: 25

Page Numbers: 7159-65

Journal Abbreviation: Oncogene

ISSN: 0950-9232

DAY: 5

MONTH: 06

YEAR: 2006

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8711562

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Keywords Mesh Terms:

KEYWORDS: Tumor Suppressor Protein p53

MESH TERMS: metabolism

Chemical & Substance for Abstract: Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Information

Substance Name: RAG-1 protein

Registry Number: 128559-51-3

Grant and Affiliation Information for Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs.

AFFILIATION: The Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, The Institute of Biotechnology, San Antonio, TX 78245-3207, USA.

Country: England

AGENCY: United States NCI

GRANT: R01 CA76317-05A1

ACRONYM: CA

MEDLINETA: Oncogene

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