...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle
【24h】

Rapid DNA-protein cross-linking and strand scission by an abasic site in a nucleosome core particle

机译:通过核小体核心颗粒中无碱基位点的快速DNA-蛋白质交联和链断裂

获取原文
获取原文并翻译 | 示例
           

摘要

Apurinic/apyrimidinic (AP) sites are ubiquitous DNA lesions that are highly mutagenic and cytotoxic if not repaired. In addition, clusters of two or more abasic lesions within one to two turns of DNA, a hallmark of ionizing radiation, are repaired much less efficiently and thus present greater mutagenic potential. Abasic sites are chemically labile, but naked DNA containing them undergoes strand scission slowly with a half-life on the order of weeks. We find that independently generated AP sites within nucleosome core particles are highly destabilized, with strand scission occurring ~60-fold more rapidly than in naked DNA. The majority of core particles containing single AP lesions accumulate DNA-protein cross-links, which persist following strand scission. The N-terminal region of histone protein H4 contributes significantly to DNA-protein crosslinks and strand scission when AP sites are produced approximately 1.5 helical turns from the nucleosome dyad, which is a known hot spot for nucleosomal DNA damage. Reaction rates for AP sites at two positions within this region differ by ~4-fold. However, the strand scission of the slowest reacting AP site is accelerated when it is part of a repair resistant bistranded lesion composed of two AP sites, resulting in rapid formation of double strand breaks in high yields. Multiple lysine residues within a single H4 protein catalyze double strand cleavage through a mechanism believed to involve a templating effect. These results show that AP sites within the nucleosome produce significant amounts of DNA-protein cross-links and generate double strand breaks, the most deleterious form of DNA damage.
机译:apurinic / apyrimidinic(AP)位点是普遍存在的DNA损伤,如果不修复,会高度致突变并具有细胞毒性。另外,在一到两回合的DNA中,两个或多个无碱基损伤的簇被修复,效率低得多,因而具有更大的诱变潜力。无碱基位点在化学上不稳定,但是包含它们的裸露DNA缓慢断裂,半衰期约为数周。我们发现,核小体核心颗粒内独立产生的AP位点高度不稳定,断链发生的速度比裸DNA快60倍。含有单个AP病变的大多数核心颗粒会积累DNA-蛋白质交联,这种断裂在链断裂后仍然存在。组蛋白H4的N端区域在从核小体二倍体产生大约1.5螺旋匝的AP位点时显着促进了DNA-蛋白交联和链断裂,这是已知的核小体DNA损伤的热点。该区域内两个位置的AP位点的反应速率相差约4倍。但是,当反应速度最慢的AP位点是由两个AP位点组成的具有抗修复性的双链病变时,它的分裂速度会加快,从而导致高产双链断裂的快速形成。单个H4蛋白中的多个赖氨酸残基通过一种被认为涉及模板效应的机制催化双链裂解。这些结果表明,核小体中的AP位点会产生大量的DNA-蛋白质交联并产生双链断裂,这是DNA损伤的最有害形式。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号