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首页> 外文期刊>The Open Cancer Journal >Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition
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Human Genetic Disorders Associated with Genome Instability, Premature Aging and Cancer Predisposition

机译：与基因组不稳定，过早衰老和癌症易感性相关的人类遗传疾病

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摘要

Our genetic material is constantly damaged by internal sources such as reactive oxygen species and externalsources such as ionizing radiation and sunlight. However, we seldom notice these injuries because our cells possesselegant DNA surveillance networks that serve to maintain cellular homeostasis. These networks are complex signaltransduction pathways that coordinate cell cycle checkpoints and DNA repair processes to eliminate DNA damage, aswell as invoking pathways such as sustained growth arrest (i.e., accelerated senescence) and apoptotic cell death toeliminate injured cells from the proliferating population. The p53 tumor suppressor protein and its downstream effectorp21 are key regulators of these various responses. Failure of cells to properly activate p53/p21-mediated events followinggenotoxic stress may lead to the development of genomic instability and the emergence of malignant cells which exhibitstem cell-like properties. It is therefore not surprising that defects in major players of the DNA surveillance networks arethe underlying cause for numerous debilitating human genetic disorders that are characterized by genomic instability,premature aging, and cancer proneness. In this article, we first provide an update on the role of the p53 signaling pathwayin determining the fate of human cells following exposure to DNA-damaging agents. We next review the clinical andlaboratory features of the most extensively studied human genome instability disorders including xerodermapigmentosum, Cockayne syndrome, ataxia telangiectasia, and Li-Fraumeni syndrome, and discuss the current knowledgeon the biological consequences of deregulated p53 signaling in cells derived from patients with such disorders.
机译：我们的遗传物质经常受到内部来源（例如活性氧）和外部来源（如电离辐射和阳光）的破坏。但是，我们很少注意到这些伤害，因为我们的细胞拥有优雅的DNA监测网络，可维持细胞体内稳态。这些网络是复杂的信号转导途径，可协调细胞周期检查点和DNA修复过程以消除DNA损伤，以及调用途径，例如持续的生长停滞（即加速衰老）和凋亡性细胞死亡，从而从增殖人群中消除受损细胞。 p53抑癌蛋白及其下游效应物p21是这些各种反应的关键调节因子。遗传毒性应激后，细胞未能正确激活p53 / p21介导的事件可能导致基因组不稳定性的发展和表现出类细胞特性的恶性细胞的出现。因此，DNA监测网络主要参与者的缺陷是许多令人衰弱的人类遗传疾病的根本原因也就不足为奇了，这些疾病的特征是基因组不稳定，过早衰老和易患癌症。在本文中，我们首先提供p53信号通路在确定DNA破坏剂暴露后确定人类细胞命运方面的作用的最新进展。接下来，我们回顾研究最广泛的人类基因组不稳定性疾病的临床和实验室特征，其中包括干皮病，Cockayne综合征，共济失调毛细血管扩张症和Li-Fraumeni综合征，并讨论有关p53信号转导异常的生物学结果的最新知识疾病。

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