Kinase-dead ATM Protein Causes Genomic Instability and Early Embryonic Lethality in Mice

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2012 Aug 8

PMID 22869596

Citations 72

Authors

Kenta Yamamoto

Yunyue Wang

Wenxia Jiang

Xiangyu Liu

Richard L Dubois

Chyuan-Sheng Lin

Thomas Ludwig

Christopher J Bakkenist

Shan Zha

Affiliations

Soon will be listed here.

Abstract

Ataxia telangiectasia (A-T) mutated (ATM) kinase orchestrates deoxyribonucleic acid (DNA) damage responses by phosphorylating numerous substrates implicated in DNA repair and cell cycle checkpoint activation. A-T patients and mouse models that express no ATM protein undergo normal embryonic development but exhibit pleiotropic DNA repair defects. In this paper, we report that mice carrying homozygous kinase-dead mutations in Atm (Atm(KD/KD)) died during early embryonic development. Atm(KD/-) cells exhibited proliferation defects and genomic instability, especially chromatid breaks, at levels higher than Atm(-/-) cells. Despite this increased genomic instability, Atm(KD/-) lymphocytes progressed through variable, diversity, and joining recombination and immunoglobulin class switch recombination, two events requiring nonhomologous end joining, at levels comparable to Atm(-/-) lymphocytes. Together, these results reveal an essential function of ATM during embryogenesis and an important function of catalytically inactive ATM protein in DNA repair.

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