• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Replication fork stability confers chemoresistance in BRCA-deficient cells
【24h】

Replication fork stability confers chemoresistance in BRCA-deficient cells

机译：复制叉的稳定性赋予BRCA缺陷细胞化学耐药性

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance.
机译：缺乏Brca1和Brca2基因的细胞通过同源重组修复DNA双链断裂的能力降低，因此对DNA破坏剂（包括顺铂和聚（ADP-核糖）聚合酶（PARP）抑制剂）过敏。在这里，我们显示MLL3 / 4复合蛋白PTIP的丢失保护了Brca1 / 2缺陷细胞免受DNA损伤，并挽救了Brca2缺陷胚胎干细胞的致死性。但是，PTIP缺乏不能在双链断裂时恢复同源重组活性。相反，它的缺失会抑制MRE11核酸酶募集到停滞的复制叉中，从而保护新生的DNA链免受广泛降解。更普遍的是，在不产生Brca2回复突变的Brca2缺陷型肿瘤细胞中，获得PARP抑制剂和顺铂耐药性与复制叉保护有关。多种蛋白（包括PARP1和CHD4）的破坏导致相同的复制叉保护终点，突显了肿瘤细胞规避化学疗法干预并获得耐药性的复杂性。

著录项

  • 来源
    《Nature》 |2016年第7612期|382-387|共6页
  • 作者

    Chaudhuri Arnab Ray; Callen Elsa; Ding Xia; Gogola Ewa; Duarte Alexandra A.; Lee Ji-Eun; Wong Nancy; Lafarga Vanessa; Calvo Jennifer A.; Panzarino Nicholas J.; John Sam; Day Amanda; Crespo Anna Vidal; Shen Binghui; Starnes Linda M.; de Ruiter Julian R.; Daniel Jeremy A.; Konstantinopoulos Panagiotis A.; Cortez David; Cantor Sharon B.; Fernandez-Capetillo Oscar; Ge Kai; Jonkers Jos; Rottenberg Sven; Sharan Shyam K.; Nussenzweig Andre;

  • 作者单位

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA|Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;

    Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands|Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;

    Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;

    NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain;

    Univ Massachusetts, Sch Med, UMASS Mem Canc Ctr, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA;

    Univ Massachusetts, Sch Med, UMASS Mem Canc Ctr, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

    City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, 1500 East Duarte Rd, Duarte, CA 91010 USA;

    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark;

    Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands|Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;

    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark;

    Harvard Med Sch, Dana Farber Canc Inst, Dept Gynecol Med Oncol, Boston, MA 02215 USA;

    Vanderbilt Univ, Dept Biochem, Sch Med, 2215 Garland Ave, Nashville, TN 37232 USA;

    Univ Massachusetts, Sch Med, UMASS Mem Canc Ctr, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA;

    Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain;

    NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA;

    Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands|Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;

    Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands|Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands|Univ Bern, Vetsuisse Fac, Inst Anim Pathol, Langgassstr 122, CH-3012 Bern, Switzerland;

    NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA;

    NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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