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首页> 外文学位 >An unexpected role for the DNA-repair protein poly (adp-ribose) polymerase I in the induction and maintenance of a pluripotent stem cell phenotype.
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An unexpected role for the DNA-repair protein poly (adp-ribose) polymerase I in the induction and maintenance of a pluripotent stem cell phenotype.

机译：DNA修复蛋白聚（核糖）聚合酶I在多能干细胞表型的诱导和维持中出乎意料的作用。

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摘要

Induced pluripotency is a genetic reprogramming technique in which adult somatic cells, such as skin fibroblasts or blood lymphocytes, are reprogrammed back to a primordial state functionally identical to embryonic stem cells (ESCs). This is accomplished using forced expression of the stem cell genes Oct3/4, Sox2, Klf4 and c-Myc, collectively referred to as the Yamanaka factors. Although the resulting induced pluripotent stem cells (iPSCs) are donor-autologous and therefore overcome the obstacles that have prevented widespread medical use of ESCs, our understanding of the mechanisms of induced pluripotency remains limited. I identified a previously unknown role for the DNA repair protein Poly (ADP-Ribose) Polymerase 1 (PARP-1) as being critical for induced pluripotency to occur. Fibroblasts deficient in this gene fail to reprogram or give rise to iPSCs, as do cells that have been treated with a PARP-1 chemical inhibitor. This same inhibitor also causes ESCs and iPSCs to lose their pluripotency. Molecular studies identify Sox2 as a mechanism by which PARP-1 regulates pluripotency, and that PARylation of Sox2 is required to maintain normal Sox2 levels. Lastly, inclusion of PARP-1 as a fifth factor supplementing the Yamanaka reprogramming repertoire results in significant enhancement in reprogramming somatic cells. Together, these findings describe a new role for PARP-1 as a master facilitator of pluripotency.
机译：诱导多能性是一种基因重编程技术，其中成年的体细胞，例如皮肤成纤维细胞或血液淋巴细胞，被重编程为功能上与胚胎干细胞（ESC）相同的原始状态。这是通过强制表达干细胞基因Oct3 / 4，Sox2，Klf4和c-Myc来完成的，这些基因统称为Yamanaka因子。尽管产生的诱导多能干细胞（iPSC）是供体自体的，因此克服了阻碍ESC在医学上广泛应用的障碍，但我们对诱导多能性机制的理解仍然有限。我确定了DNA修复蛋白聚（ADP-核糖）聚合酶1（PARP-1）的一个以前未知的作用，它对于诱导多能性的发生至关重要。缺乏该基因的成纤维细胞不能重编程或产生iPSC，就像用PARP-1化学抑制剂处理过的细胞一样。相同的抑制剂也会导致ESC和iPSC失去多能性。分子研究确定Sox2是PARP-1调节多能性的机制，并且维持Sox2正常水平需要Sox2的PARylation。最后，将PARP-1作为补充Yamanaka重编程库的第五种因素，导致体细胞重编程显着增强。总之，这些发现描述了PARP-1作为多能性的主要促进者的新角色。

著录项

  • 作者

    Williams, Ambrose Jon.;

  • 作者单位

    University of California, Davis.;

  • 授予单位 University of California, Davis.;
  • 学科 Biology Molecular.;Engineering Biomedical.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 101 p.
  • 总页数 101
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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