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ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks.

Abstract：

:The ATM (ataxia telangiectasia mutated) protein plays a central role in sensing and responding to DNA double-strand breaks. Lymphoid cells are unique in undergoing physiologic double-strand breaks in the processes of Ig class switch recombination and T or B cell receptor V(D)J recombination, and a role for ATM in these processes has been suggested by clinical observations in ataxia telangiectasia patients as well as in engineered mice with mutations in the Atm gene. We demonstrate here a defect in thymocyte maturation in ATM-deficient mice that is associated with decreased efficiency in V-J rearrangement of the endogenous T cell receptor (TCR)alpha locus, accompanied by increased frequency of unresolved TCR Jalpha coding end breaks. We also demonstrate that a functionally rearranged TCRalphabeta transgene is sufficient to restore thymocyte maturation, whereas increased thymocyte survival by bcl-2 cannot improve TCRalpha recombination and T cell development. These data indicate a direct role for ATM in TCR gene recombination in vivo that is critical for surface TCR expression in CD4(+)CD8(+) cells and for efficient thymocyte selection. We propose a unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCRalpha locus. In the absence of ATM, delayed TCRalpha coding joint formation results both in a reduction of alphabeta TCR-expressing immature cells, leading to inefficient thymocyte selection, and in accumulation of unstable open chromosomal DNA breaks, predisposing to TCRalpha locus-associated chromosomal abnormalities.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Vacchio MS,Olaru A,Livak F,Hodes RJ

doi

10.1073/pnas.0611222104

subject

Has Abstract

pub_date

2007-04-10 00:00:00

pages

6323-8

issue

15

eissn

0027-8424

issn

1091-6490

pii

0611222104

journal_volume

104

pub_type

杂志文章

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