ATM-mediated response to DNA double strand breaks in human neurons derived from stem cells

被引:33
作者
Biton, Sharon
Gropp, Michal
Itsykson, Pavel
Pereg, Yaron
Mittelman, Leonid
Johe, Karl
Reubinoff, Benjamin
Shiloh, Yosef [1 ]
机构
[1] Tel Aviv Univ, David & Inez Myers Lab Genet Res, Dept Mol Genet & Biochem, Sackler Sch Med, IL-69978 Tel Aviv, Israel
[2] Hadassah Univ Hosp, Hadassah Human Embryon Stem Cell Res Ctr, Goldyne Savad Inst Gene Therapy, IL-91120 Jerusalem, Israel
[3] Tel Aviv Univ, Interdepartmental Core Facil, Sackler Sch Med, IL-69978 Tel Aviv, Israel
[4] Neuralstem Inc, Rockville, MD 20850 USA
关键词
ataxia-telangiectasia; ATM; DNA damage response; embryonic stem cells; neural stem cells; neurons;
D O I
10.1016/j.dnarep.2006.10.019
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Ataxia-telangiectasia (A-T) is a multi-system genomic instability syndrome that is caused by loss or inactivation of the ATM protein kinase. ATM is largely nuclear in proliferating cells, and activates an extensive network of pathways in response to double strand breaks (DSBs) in the DNA by phosphorylating key proteins in these pathways. The prominent symptom of A-T is neuronal degeneration, making the elucidation of ATM's functions in neurons essential to understanding the disease. It has been suggested that ATM is cytoplasmic in neurons and functions in processes that are not associated with the DNA damage response. Recently we showed that in human neuron-like cells obtained by in vitro differentiation of neuroblastomas, ATM was largely nuclear and mediated the DSB response as in proliferating cells. We have now extended these studies to two additional model systems: neurons derived from human embryonic stem cells, and cortical neurons derived from neural stem cells. The results substantiate the notion that ATM is nuclear in human neurons and mediates the DSB response, the same as it does in proliferating cells. We present here unique and powerful model systems to further study the ATM-mediated network in neurons. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:128 / 134
页数:7
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