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PNAS:探究DNA修复过程帮助开发更好的癌症疗法

来源:生物谷 2013-10-02 18:57

2013年10月2日讯 /生物谷BIOON/--通过了解修复DNA断裂所需的详细过程,杜克大学癌症研究所科学家们更好地理解了细胞如何处理接二连三的损害(这些损害可以促进癌症和其他疾病)。

相关研究论文发表在2013年9月30日的PNAS杂志上,研究人员集中在一系列复杂的细胞事件,即细胞定期修复由阳光照射,吸烟,甚至正常新陈代谢引发的DNA损伤。如果不能正确地修复,DNA断裂可导致细胞损伤,从而导致癌症。

杜克大学癌症研究所执行董事Michael Kastan博士说:我们从未很好的分析测量DNA断裂如何被修复,也没有很好的工具在分子水平上研究维修如何展开。我们的工作第一次让我们,可以灵敏测量DNA断裂的修复,并研究它们发生的分子机制。

细胞内的DNA面临一个挑战,即自我修复。紧紧包裹在一个复杂蛋白质即染色质中,DNA就像卷轴一样绕在蛋白质结构核小体上。Kastan和同事开发的系统诱导DNA链上指定点发生DNA断裂,使研究人员能够看清细胞修复过程的关键事件。

他们首次描述了一个精心设计的互动过程,当一个关键蛋白质核仁蛋白被招募到破损部位,破坏核小体时,轴紧紧缠绕的受损DNA会暂时放松。然后当修复完整后核小体被重新形成时,该过程会被逆转。

研究第一次表明核小体的破坏在DNA修复功能中的重要性,Kastan说,这个核小体的破坏,使DNA修复蛋白“访问”DNA损伤部位,并开始修补破损过程。Kastan说,这一发现为细胞如何保持健康,以及修复过程如何可能被操纵提供了重要见解。例如,可以针对核仁蛋白开发出新的癌症疗法,提高肿瘤细胞对放疗或化疗的敏感性。(生物谷Bioon.com)

Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair

Michael Goldstein,et al.

Recruitment of DNA repair factors and modulation of chromatin structure at sites of DNA double-strand breaks (DSBs) is a complex and highly orchestrated process. We developed a system that can induce DSBs rapidly at defined endogenous sites in mammalian genomes and enables direct assessment of repair and monitoring of protein recruitment, egress, and modification at DSBs. The tight regulation of the system also permits assessments of relative kinetics and dependencies of events associated with cellular responses to DNA breakage. Distinct advantages of this system over focus formation/disappearance assays for assessing DSB repair are demonstrated. Using ChIP, we found that nucleosomes are partially disassembled around DSBs during nonhomologous end-joining repair in G1-arrested mammalian cells, characterized by a transient loss of the H2A/H2B histone dimer. Nucleolin, a protein with histone chaperone activity, interacts with RAD50 via its arginine-glycine rich domain and is recruited to DSBs rapidly in an MRE11-NBS1-RAD50 complex-dependent manner. Down-regulation of nucleolin abrogates the nucleosome disruption, the recruitment of repair factors, and the repair of the DSB, demonstrating the functional importance of nucleosome disruption in DSB repair and identifying a chromatin-remodeling protein required for the process. Interestingly, the nucleosome disruption that occurs during DSB repair in cycling cells differs in that both H2A/H2B and H3/H4 histone dimers are removed. This complete nucleosome disruption is also dependent on nucleolin and is required for recruitment of replication protein A to DSBs, a marker of DSB processing that is a requisite for homologous recombination repair.

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