生物谷报道：此前，人类XPF基因的突变一直被与温和型的早衰（progeria）联系在一起。现在，研究人员在一个15岁的男孩身上识别出了一个以前不知道的、引起严重早衰的XPF突变（XFE）。这一发现发表于12月21日出版的《Nature》杂志上。
XPF的这一突变体形式的性质表明，两个关于衰老过程的看似根本不相同的理论可能是一致的。有些人认为，衰老是由基因调控的；另一些人认为，衰老是由于DNA损伤的逐渐积累。这两种观点可能都是正确的。研究人员用遗传工程方法来模拟具有XPF突变症状的年轻小鼠，这种小鼠表现出正常年老小鼠的很多特征。这些特征包括诱导产生的胰岛素信号作用、细胞死亡增加、以及高抗氧化剂水平和高DNA修复活性。这些发现与DNA损伤来自与衰老相关的功能下降的一个模型是一致的，但遗传学规律（尤其是对胰岛素信号通道而言）影响损伤积累的速度有多快以及功能损失的速度有多快。该发现的一个意义是，通过增强DNA修复体系，也许有可能延长寿命或改善老年时的身体适应性。
FIGURE 1. Molecular characterization of progeroid patient 'XFE'.
a, Clonogenic survival assay measuring UV-radiation sensitivity of wild-type (WT), XFE and xeroderma pigmentosum patient primary fibroblasts (XP-F, XP-C and XP-A). b, RNA synthesis recovery after UV irradiation of patient fibroblasts. c, Immunodetection of XPF in nuclear extracts of patient fibroblasts (normal C5RO, mild xeroderma pigmentosum patient XP42RO and patient XFE). Cross-reacting bands demonstrate equal protein loading. d, Immunodetection of ERCC1 in the same samples. e, Clonogenic survival assay measuring sensitivity of patient fibroblasts to the crosslinking agent mitomycin C. Error bars (a, b, e) indicate s.e.m. of three experiments.
原文出处：
Nature Volume 444 Number 7122 21 December 2006
A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis p1038
Laura J. Niedernhofer, George A. Garinis, Anja Raams, Astrid S. Lalai, Andria Rasile Robinson, Esther Appeldoorn, Hanny Odijk, Roos Oostendorp, Anwaar Ahmad, Wibeke van Leeuwen, Arjan F. Theil, Wim Vermeulen, Gijsbertus T. J. van der Horst, Peter Meinecke, Wim J. Kleijer, Jan Vijg, Nicolaas G. J. Jaspers and Jan H. J. Hoeijmakers
doi:10.1038/nature05456
Abstract | Full Text | PDF (1,002K) | Supplementary information
See also: Editor's summary | News and Views by Kirkwood
相关基因：
XPF
xeroderma pigmentosum, complementation group F [Homo sapiens]
GeneID: 7509
This record was replaced with GeneID: 2072
作者简介：
Laura J. Niedernhofer - Assistant Professor
Webpage:
http://www.mgb.pitt.edu/personnel/view.asp?uid=niedernh
Jan H.J. Hoeijmakers
Jan Hoeijmakers did his PhD thesis with Piet Borst at the University of Amsterdam on trypanosomes, the causative agent of sleeping sickness. He studied the structure and function of the fishnet-shaped kinetoplast mt DNA and discovered the mechanism of gene duplication-transposition underlying antigenic variation that enables trypanosomes to escape from immune surveillance. In 1981 he joined the group of Dirk Bootsma at the Erasmus University in Rotterdam to start molecular analysis of DNA repair in mammals. Since 1993 he is professor in molecular genetics and since 1999 head of the Institute of Genetics. His group cloned the first human DNA repair gene, discovered the strong evolutionary conservation of DNA repair pathways, unravelled the function of a number of the components and elucidated the basis of several human DNA repair syndromes. The unexpected dual function of repair/transcription factor TFIIH was disclosed (together with Jean-Marc Egly), which led to a novel concept in human genetics: transcription-repair syndromes. His group explored the in vivo analysis of DNA repair using confocal microscopy and sophisticated laser photobleaching techniques and revealed the highly dynamic nature and basic principles of the organization of repair processes in living cells. The insight gained in these studies extends to other key processes including transcription, replication and recombination. A systematic investment was made in the generation of mouse mutants for a large number of repair genes, in many cases mimicking mutations found in human patients in order to be able to directly compare the phenotype of the mouse with that of the corresponding human syndrome. Mouse models for the above disorders revealed a strong relationship between DNA damage, compromised repair and accelerated ageing. Using microarray analysis an important connection was disclosed between persisting DNA damage and control of the somatotrophic axis that regulates metabolism and growth, explaining the severe developmental symptoms of several of the repair syndromes. This new link has a profound impact on the understanding of the molecular basis of ageing and life span extension. Using mouse mutants with dramatically fast ageing compounds were identified that appear to protect from DNA damage and extend lifespan. On this basis a start-up company called ‘DNage’ was founded to provide rational solutions to medical/health care problems associated with ageing. The first focus will be to preventing premature aging symptoms in progeroid disorders with the ultimate goal to counteract the onset of a broad spectrum of ageing-related diseases in the normal population. Finally, his group generated the first mouse mutant without biological clock opening a new line of research in this area.
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Address
Molecular basis and biological impact of genome (in)stability
DNA damage and genome care-takers
Nucleotide excision repair as a model repair process
Human NER disorders display extreme clinical heterogeneity
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