O'Driscoll Mark, Jeggo Penny A
Genome Damage and Stability Centre, University of Sussex, Brighton, East Sussex BN1 9RQ, UK.
DNA Repair (Amst). 2008 Jul 1;7(7):1039-50. doi: 10.1016/j.dnarep.2008.03.018. Epub 2008 May 23.
A network of DNA damage response (DDR) mechanisms functions co-ordinately to maintain genomic stability and ensure cellular survival in the face of exogenous and endogenous DNA damage. Defects in DDR pathways have been identified in a range of human disorders, collectively classified as DDR-defective syndromes. A common feature of these syndromes is a predisposition to cancer demonstrating the importance of the DDR in cancer avoidance. How the DDR mechanisms serve to maintain genomic stability has been the predominant focus of research into their function. However, many DRR-defective syndromes are also characterised by impaired development demonstrating broader roles for the DDR mechanisms. Microcephaly, representing reduced brain size, is a feature common to a diverse range of DDR-defective disorders. Microcephaly is most likely caused by loss (increased cell death) or failure of the developing neuronal stem cells or their progenitors to divide suggesting a fundamental role for the DDR in maintaining proliferative potential in the developing nervous system. Currently, it is unclear why the DDR proteins should be more important during neuronal development compared with the development of other tissues or why the embryonic brain is more sensitive than the adult brain. Here, we overview the DDR-defective disorders in the context of microcephaly and discuss a model underlying this striking phenotype.
一个DNA损伤反应（DDR）机制网络协同发挥作用，以维持基因组稳定性，并确保细胞在面对外源性和内源性DNA损伤时存活。DDR途径的缺陷已在一系列人类疾病中被发现，这些疾病统称为DDR缺陷综合征。这些综合征的一个共同特征是易患癌症，这表明DDR在预防癌症方面的重要性。DDR机制如何维持基因组稳定性一直是其功能研究的主要焦点。然而，许多DDR缺陷综合征的特征还包括发育受损，这表明DDR机制具有更广泛的作用。小头畸形表现为脑容量减小，是多种DDR缺陷疾病的共同特征。小头畸形很可能是由于发育中的神经干细胞或其祖细胞丢失（细胞死亡增加）或无法分裂所致，这表明DDR在维持发育中的神经系统的增殖潜力方面具有重要作用。目前尚不清楚为什么DDR蛋白在神经元发育过程中比在其他组织发育过程中更重要，也不清楚为什么胚胎脑比成体脑更敏感。在这里，我们在小头畸形的背景下概述DDR缺陷疾病，并讨论这种显著表型背后的模型。
