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首页> 外文期刊>Nucleic Acids Research >Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair
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Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair

机译：FANCONI贫血信号和MUS81配合保障开发和交联维修

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摘要

Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair. The relationship of this repair defect to disease traits remains unclear, given that crosslink sensitivity is recapitulated in FA mouse models without most of the other disease-related features. Mice deficient in Mus81 are also defective in crosslink repair, yet MUS81 mutations have not been linked to FA. Using mice deficient in both Mus81 and the FA pathway protein FancC, we show both proteins cooperate in parallel pathways, as concomitant loss of FancC and Mus81 triggered cell-type-specific proliferation arrest, apoptosis and DNA damage accumulation in utero. Mice deficient in both FancC and Mus81 that survived to birth exhibited growth defects and an increased incidence of congenital abnormalities. This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity. Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.
机译：与范可尼贫血（FA）的个体易受骨髓衰竭，先天性畸形，癌症易感性和表现出缺陷的DNA交联的修复。因为交联灵敏度在足总杯小鼠模型概括而不大多数其他疾病相关功能的这种修复缺陷病性状的关系尚不清楚。在MUS81缺陷的小鼠也是交联修复有缺陷的，但MUS81突变还没有被链接到FA。在这两个MUS81和FA通路蛋白FANCC使用缺陷小鼠，我们表明这两种蛋白在平行路径进行合作，为FANCC和MUS81的同时损失引发的细胞类型特异性增殖抑制，细胞凋亡和DNA损伤的积累在子宫内。缺陷的小鼠均FANCC和MUS81存活到出生呈现的生长缺陷，并增加先天性畸形的发生。这在发育结果FANCC和MUS81的协同性也反映响应于交联损伤和染色体完整性。因此，我们的研究结果表明，对DNA损伤两种途径保障超过临界阈值触发细胞增殖和凋亡，导致在子宫内发育受到影响。

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