DNA repair is limiting for haematopoietic stem cells during ageing

被引：420

作者：

Nijnik, Anastasia

Woodbine, Lisa

Marchetti, Caterina

Dawson, Sara

Lambe, Teresa

Liu, Cong

Rodrigues, Neil P.

Crockford, Tanya L.

Cabuy, Erik

Vindigni, Alessandro

Enver, Tariq

Bell, John I.

Slijepcevic, Predrag

Goodnow, Christopher C.

Jeggo, Penelope A. ^{[1
]}

Cornall, Richard J.

机构：

[1] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England

[2] Univ Oxford, Oxford OX3 9DU, England

[3] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy

[4] Australian Natl Univ, Australia & Australian Phenom Facil, Australian Canc Res Fdn Genet Lab, John Curtin Sch Med Res, Canberra, ACT 2601, Australia

[5] Univ Oxford, Weatherall Inst Mol Med, Oxford OX3 9DS, England

[6] Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Uxbridge UB8 3PH, Middx, England

来源：

NATURE | 2007年 / 447卷 / 7145期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1038/nature05875

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4(Y288C) mutation. The Lig4(Y288C) mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome, showing immunodeficiency and growth retardation. Diminished DNA double-strand break repair in the Lig4(Y288C) strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing, and severely impairs stem cell function in tissue culture and transplantation. The sensitivity of haematopoietic stem cells to non-homologous end-joining deficiency is therefore a key determinant of their ability to maintain themselves against physiological stress over time and to withstand culture and transplantation.

引用

页码：686 / U9

页数：6

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