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首页> 外文学位 >Genomic instability, cancer predisposition and premature aging in a mouse model of Rothmund-Thomson Syndrome.
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Genomic instability, cancer predisposition and premature aging in a mouse model of Rothmund-Thomson Syndrome.

机译：Rothmund-Thomson综合征小鼠模型中的基因组不稳定性，癌症易感性和过早衰老。

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摘要

RecQ DNA helicases have important roles in the maintenance of genome stability. Recql4, one of five mammalian RecQ DNA helicases, is the mouse orthologue of the disease-causing gene, RECQL4, of Type II Rothmund-Thomson Syndrome (RTS). Type-II RTS patients have abnormalities of the skin and skeleton and increased risk for developing osteosarcoma. Karyotypic analyses of Type II patient-derived cells demonstrate unusually high frequencies of chromosomal aberrations including aneuploidy. While chromosomal instability likely contributes to the patients increased susceptibility to osteosarcoma, the nature of genomic instability induced by RECQL4 deficiency and the disease etiology of RTS remains elusive. We generated Recql4-deficient mice, and demonstrate here that they are viable and manifest the hallmark features of RTS, including developmental defects of skeleton, skin pigmentation defects, genomic instability and predisposition to cancer. Specifically, Recql4-deficient mice have skeletal defects of the palate and limbs, display premature onset degenerative joint defects and osteoporosis, spontaneously acquire several abnormalities of the skin, including premature alopecia and graying of fur. One striking skin phenotype is an induced hyper-pigmentation associated with premature photo-aging upon treatment with low dose ultraviolet light. Cellular analyses derived from these mice revealed defects in chromosome segregation and aneuploidy resulting from precocious loss of sister-chromatid cohesion. Thus, mammalian Recql4 has a critical role in sister-chromatid cohesion and in the maintenance of euploidy and that Recql4-deficient mice manifest a premature aging-like syndrome that shares phenotypic features with RTS patients and the elderly.
机译：RecQ DNA解旋酶在维持基因组稳定性中具有重要作用。 Recql4是五个哺乳动物RecQ DNA解旋酶之一，是II型Rothmund-Thomson综合征（RTS）致病基因RECQL4的小鼠直系同源基因。 II型RTS患者的皮肤和骨骼异常，患骨肉瘤的风险增加。 II型患者来源细胞的核型分析显示异常高频率的染色体畸变，包括非整倍性。尽管染色体不稳定可能导致患者对骨肉瘤的敏感性增加，但RECQL4缺乏引起的基因组不稳定的性质以及RTS的疾病病因仍然难以捉摸。我们生成了Recql4缺陷型小鼠，并在此处证明它们是可行的，并表现出RTS的标志性特征，包括骨骼发育缺陷，皮肤色素沉着缺陷，基因组不稳定和易患癌症。具体来说，Recq14缺陷型小鼠具有and骨和四肢的骨骼缺陷，表现出过早的退化性关节缺损和骨质疏松症，自发获得皮肤的一些异常，包括过早的脱发和皮毛变灰。一种醒目的皮肤表型是在用低剂量紫外线治疗后与过早的光老化相关的诱导的色素沉着过度。从这些小鼠获得的细胞分析结果显示，由于姐妹染色单体凝聚力的过早丧失而导致染色体分离和非整倍性缺陷。因此，哺乳动物Recql4在姐妹染色单体凝聚力和整倍性的维持中起着关键作用，而Recql4缺陷型小鼠表现出与RTS患者和老年人共享表型特征的早衰样综合征。

著录项

  • 作者

    Mann, Michael Bruce.;

  • 作者单位

    Case Western Reserve University (Health Sciences).;

  • 授予单位 Case Western Reserve University (Health Sciences).;
  • 学科 Biology Genetics.; Health Sciences Oncology.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 278 p.
  • 总页数 278
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 遗传学;肿瘤学;细胞生物学;
  • 关键词

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