生物通报道：细胞内的正常代谢活动会引起DNA损伤，这个速率是每个细胞每天50,000至500,000处分子损害，如果一个关键的癌症相关基因受到未修复的损伤将给机体带来灾难性的后果，因此DNA损伤一直以来也是癌症研究的一个重要方面。来自耶鲁大学医学院治疗放射学系，麻省理工癌症研究中心，Mayo临床医学院（Mayo Clinic College of Medicine），密歇根大学医学院等处的研究人员发现了一个新的DNA损伤应答蛋白，这个蛋白介导了许多信号途径，在细胞对于遗传毒性压力的应答方面扮演着一个关键的角色。这对于深入理解DNA损伤信号途径，以及癌症研究等方面具有重要的意义。

这一研究成果公布在最新一期的《Cell》杂志上，文章的通讯作者是来自耶鲁大学医学院的陈俊杰教授，其早年毕业于复旦大学遗传与遗传工程系。

以DNA为模板按碱基配对进行DNA复制是一个严格而精确的事件，但也不是完全不发生错误的。碱基配对的错误频率约为10-1－10-2，在DNA复制酶的作用下碱基错误配对频率降到约10-5－10-6，复制过程中如有错误的核苷酸参入，DNA聚合酶还会暂停催化作用，以其3’→5’外切核酸酶的活性切除错误接上的核苷酸，然后再继续正确的复制，这种校正作用广泛存在于原核和真核的DNA聚合酶中，可以说是对DNA复制错误的修复形式，从而保证了复制的准确性。

目前对真核细胞的DNA修复的反应类型、参与修复的酶类和修复机制了解还不多，但DNA损伤修复与细胞突变、寿命、衰老、肿瘤发生、辐射效应、某些毒物的作用都有密切的关系。人类遗传性疾病已发现4000多种，其中不少与DNA修复缺陷有关，这些DNA修复缺陷的细胞表现出对辐射和致癌剂的敏感性增加。

在体内，DNA损伤信号利用了许多翻译后修饰作为分子开关，用于细胞周期检测点，DNA修复，细胞衰老和程序性死亡的调控。虽然在这一方面进行的研究很多，但是科学家们仍然对于DNA损伤应答没有获得细致深入的了解。

在这篇文章中，研究人员发现RNF8——一个FHA/RING结构域包含蛋白，在早期DNA损伤应答中扮演着一个关键的角色。他们在获得了FHA结构域结构的X射线晶体结构（1.35 Å）之后，经分析发现RNF8有利于检测点介导蛋白BRCA1和53BP1在损伤染色体上的积累，这主要通过两个方面，一方面是磷酸依赖性FHA位点介导的RNF8结合到MDC1上，另一方面则是通过RNF8在H2AX及其它损伤位点底物的泛素化过程中的作用。

而且研究人员也发现RNF8敲除的细胞存在G2/M检测点缺陷，并且IR敏感性增加。总而言之，这些研究结果都说明RNF8是一种新DNA损伤应答蛋白，介入了蛋白磷酸化及泛素信号途径，在细胞对于遗传毒性压力的应答方面扮演着一个关键的角色。
（生物通：张迪）

原文检索：
Cell, Vol 131, 901-914, 30 November 2007
RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly
『Abstract』

附：
Junjie Chen, PhD
Professor, Department of Therapeutic Radiology
junjie.chen@yale.edu

Yale University School of Medicine
Department of Therapeutic Radiology

Degrees/Education:
B.S., Genetics and Genetic Engineering, Fudan University, Shanghai, People’s Republic of China (1988)
Ph.D., Cell and Molecular Biology Program, University of Vermont (1994)
Post Doctoral Fellow, Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School (1996)
Post Doctoral Fellow, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School (1999)

Faculty Appointments:
Assistant Professor, Mayo Clinic College of Medicine, Biochem/Molecular Biology (dates-from-1999 to 2003)
Associate Professor, Mayo Clinic College of Medicine, Pharmacology (dates- from-2004 to 2006)
Professor, Yale University School of Medicine, Therapeutic Radiology (2006-present)

Certifications/Honors:
DOD breast cancer research career Development award
DOD Breast Cancer Research Program-Era of Hope Scholar Award

Research Interests:
We are interested in the molecular mechanisms that control genomic stability, tumor suppression and longevity.

Genomic instability is a common feature of all human cancers. The maintenance of genomic integrity following DNA damage depends on the coordination of the DNA repair system and cell cycle checkpoint controls. Similar to mitogenic signaling pathways, the DNA damage-induced signaling pathway consists of kinase-dependent signaling cascades that regulate cell cycle progression, DNA repair and apoptosis following DNA damage. It is the coordination of these events that ensures genomic stability. We have just begun to understand how this coordination is accomplished in mammalian cells.

ATM (ataxia telangiectasia mutated protein) and ATR (ataxia telangiectasia-related protein), two phosphatidylinositol 3-kinase-related protein kinases, are essential components in this DNA damage-signaling pathway. ATM and ATR activate the downstream checkpoint kinases Chk1 and Chk2/Cds1. Collectively, these four protein kinases phosphorylate a number of downstream effector proteins, including tumor suppressors p53 and BRCA1, where they coordinate DNA repair, cell cycle progression, transcriptional regulation and apoptosis in response to various DNA-damaging events. By focusing on several key regulators (ATM, 53BP1, Chk2, MDC1 and BRCA1) in this pathway and using biochemical and genetic approaches, we attempt to understand the roles of this DNA damage pathway in tumorigenesis and in anti-tumor therapy.

In the last two years, we have also our interests to the roles of mitotic checkpoint control and telomere maintenance in genomic instability. Additionally, we have ongoing research pursuing the link between DNA damage/repair, the regulation of chromatin structures and aging. Overall, the lab is interested in the pathways that control genomic stability and how the dysregulation of these pathways contributes to cancer, aging and other common illnesses.