关注干细胞与DNA修复

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报道：6月7日出版的Nature杂志发表了两项重要的干细胞研究成果，一项是研究人员将皮肤细胞重新编程转换成干细胞，另外一项则是干细胞与衰老之间的关系研究。

原始出处：

Nature 447, 686-690 (7 June 2007) | doi:10.1038/nature05875; Received 5 February 2007; Accepted 24 April 2007


DNA repair is limiting for haematopoietic stem cells during ageing
Anastasia Nijnik1, Lisa Woodbine2, Caterina Marchetti2,3, Sara Dawson4, Teresa Lambe1, Cong Liu2, Neil P. Rodrigues5, Tanya L. Crockford1, Erik Cabuy6, Alessandro Vindigni3, Tariq Enver5, John I. Bell1, Predrag Slijepcevic6, Christopher C. Goodnow4,7, Penelope A. Jeggo2,7 & Richard J. Cornall1,7

Henry Wellcome Building for Molecular Physiology, Oxford University, Oxford OX3 9DU, UK
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy
Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University, Australia & Australian Phenomics Facility, Canberra, ACT 2601, Australia
Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK
Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge UB8 3PH, UK
These authors contributed equally to this work.
Correspondence to: Penelope A. Jeggo2,7Richard J. Cornall1,7 Correspondence and requests for materials should be addressed to P.A.J. (Email: p.a.jeggo@sussex.ac.uk) or R.J.C. (Email: richard.cornall@ndm.ox.ac.uk).

Abstract

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 Lig4Y288C mutation. The Lig4Y288C 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 Lig4Y288C 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.

[NextPage]
Nature 447, 725-729 (7 June 2007) |
doi:10.1038/nature05862; Received 23 January 2007; Accepted 18 April 2007
Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age


  DNA受损累积会导致成人干细胞耗竭，从而引起衰老，这被认为是首要的一条衰老机制。人体自身有着各种防御DNA受损和修复DNA的机制，但是这个机制会随着年龄的增长而逐渐衰退，在2005年的一项日本科学发表在Science杂志上的文章用动物实验证明细胞内线粒体DNA的损伤不断增加是老化的原因之一，也证明了这一观点。

  而本期Nature上的这两篇文章则提出了关于衰老的一个重要假设机制，即由于DNA损伤修复缺陷而造成的维持组织平衡的能力下降。

  在第一篇文章中，来自英国牛津大学，萨塞克斯大学（University of Sussex），意大利遗传工程和生物技术国际中心（International Centre for Genetic Engineering and Biotechnology）等处的研究人员发现由于非同源端接通道（non-homologous end-joining）的DNA修复功能失常，DNA损伤会在体内的生理条件下在干细胞中累积，导致成人干细胞随着时间的推移被耗尽。

  因此他们认为造血干细胞对于非同源端接通道缺陷的这种敏感性是其维持对抗生理压力，以及在培养和移植过程中受到的损伤的这种能力的一个关键决定因素。

  在第二篇文章中，来自斯坦福大学医学院，美国国立健康研究院，荷兰等处的研究人员发现了在三种不同的小鼠基因组（核苷切除修复，端粒修复，非同源端接通道）维护缺陷情况下与年龄相关的