核酸酶缺陷型FEN-1阻断Rad51/BRCA1介导的修复并导致三核苷酸重复序列不稳定。
Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability.
作者信息
Spiro Craig, McMurray Cynthia T
机构信息
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
出版信息
Mol Cell Biol. 2003 Sep;23(17):6063-74. doi: 10.1128/MCB.23.17.6063-6074.2003.
Abstract
Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to instability. In cells with no endogenous defects in DNA repair, exogenous nuclease-defective FEN-1 causes repeat instability and aberrant DNA repair. Inefficient flap processing blocks the formation of Rad51/BRCA1 complexes but invokes repair by other pathways.
摘要
先前的研究表明，易于扩增的重复序列会形成抑制人类瓣状核酸内切酶（FEN-1）的结构。我们在此报告，FEN-1的错误加工会引发哺乳动物细胞中的重复序列不稳定性。与纯合野生型小鼠相比，亨廷顿舞蹈病小鼠中FEN-1杂合的疾病长度CAG序列在代际遗传过程中显示出扩增而非收缩的倾向。此外，对于表达核酸酶缺陷型FEN-1的人类细胞，我们提供了直接证据，即未加工的FEN-1底物是不稳定性的前体。在DNA修复无内源性缺陷的细胞中，外源性核酸酶缺陷型FEN-1会导致重复序列不稳定性和异常的DNA修复。低效的瓣状加工会阻止Rad51/BRCA1复合物的形成，但会引发其他途径的修复。
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