Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

译文

FEN1基因的功能缺陷已被认为可导致基因组不稳定和癌症易感性。我们在人类癌症标本中鉴定出一组FEN1突变。大多数这些突变废除了皮瓣内切核酸酶1(FEN1)的三种核酸酶活性中的两种。为了证明这些体细胞突变的病因学意义,我们引入了携带E160D突变的小鼠品系,该E160D突变代表在人类癌症中鉴定出的突变。核酸酶活性的选择性消除导致凋亡细胞中频繁的自发突变和不完全消化的DNA片段的积累。突变小鼠易患自身免疫,慢性炎症和癌症。突变表型导致癌症的开始,而慢性炎症则促进癌症的发展。目前的工作例证了研究癌症发展中个体多态性和体细胞突变机制的方法,并可作为通过抑制炎症反应开发新的治疗方案的参考。

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