Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice

Jan-Willem F Theunissen; Mark I Kaplan; Patricia A Hunt; Bret R Williams; David O Ferguson; Frederick W Alt; John H J Petrini

doi:10.1016/S1097-2765(03)00455-6

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Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice

Journal article

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Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice

Jan-Willem F Theunissen, Mark I Kaplan, Patricia A Hunt, Bret R Williams, David O Ferguson, Frederick W Alt and John H J Petrini

Molecular cell, Vol.12(6), pp.1511-1523

12/2003

DOI: https://doi.org/10.1016/S1097-2765(03)00455-6

Handle:

https://hdl.handle.net/2376/112604

PMID: 14690604

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https://doi.org/10.1016/S1097-2765(03)00455-6View

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Abstract

Fibroblasts - physiology

Humans

Tumor Suppressor Protein p53 - genetics

DNA-Binding Proteins - metabolism

Lymphoma - metabolism

MRE11 Homologue Protein

Fertility

Karyotyping

Female

Chromosomal Instability

Cells, Cultured

Tumor Suppressor Protein p53 - metabolism

Survival Rate

DNA Repair Enzymes

DNA-Binding Proteins - genetics

Pregnancy

Embryo, Mammalian - physiology

Animals

Cell Cycle - physiology

Ataxia Telangiectasia - genetics

Fibroblasts - cytology

Mice

DNA Damage

Chromosomes, Mammalian - metabolism

Genes, cdc

In this study, mice expressing one of the two Mre11 alleles inherited in the human ataxia-telangiectasia like disorder (A-TLD) were derived. The mutation had a profound maternal effect on embryonic viability, revealing an acute requirement for Mre11 complex function in early embryogenesis. Mre11(ATLD1/ATLD1) mice exhibited several indices of impaired ATM function. The mice also exhibited pronounced chromosomal instability. Despite this phenotypic spectrum, the animals were not prone to malignancy. These data indicate that defective cell cycle checkpoints and chromosomal instability are insufficient to significantly enhance the initiation of tumorigenesis. In contrast, the latency of malignancy in p53(+/-) mice was dramatically reduced. We propose that in Mre11(ATLD1/ATLD1) mice, genome instability and cell cycle checkpoint defects reduce viability in early embryos and in proliferating cells, while promoting malignancy in the context of an initiating lesion.

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Title: Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice
Creators: Jan-Willem F Theunissen - Molecular Biology Program, Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences, New York, NY 10021, USA
Mark I Kaplan
Patricia A Hunt
Bret R Williams
David O Ferguson
Frederick W Alt
John H J Petrini
Publication Details: Molecular cell, Vol.12(6), pp.1511-1523
Publisher: United States
Grant note: CA92625 / NCI NIH HHS HD37502 / NICHD NIH HHS K08 HL67580 / NHLBI NIH HHS GM59413 / NIGMS NIH HHS AI35714 / NIAID NIH HHS
Identifiers: 99900548048501842
Language: English
Resource Type: Journal article