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Stalled replication forks within heterochromatin require ATRX for protection

机译：异染色质中停滞的复制叉需要ATRX进行保护

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Expansive growth of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered neocortex, while also placing a heavy burden on proteins that regulate chromatin packaging and genome integrity. This problem is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. ATRX gene mutations cause a severe intellectual disability disorder ( α -thalassemia mental retardation X-linked (ATRX) syndrome; OMIM no. 301040), characterized by microcephaly, urogenital abnormalities and α -thalassemia. Although the ATRX protein is required for the maintenance of repetitive DNA within heterochromatin, how this translates to disease pathogenesis remain poorly understood and was a focus of this study. We demonstrate that Atrx FoxG1Cre forebrain-specific conditional knockout mice display poly(ADP-ribose) polymerase-1 (Parp-1) hyperactivation during neurogenesis and generate fewer late-born Cux1- and Brn2-positive neurons that accounts for the reduced cortical size. Moreover, DNA damage, induced Parp-1 and Atm activation is elevated in progenitor cells and contributes to their increased level of cell death. ATRX-null HeLa cells are similarly sensitive to hydroxyurea-induced replication stress, accumulate DNA damage and proliferate poorly. Impaired BRCA1-RAD51 colocalization and PARP-1 hyperactivation indicated that stalled replication forks are not efficiently protected. DNA fiber assays confirmed that MRE11 degradation of stalled replication forks was rampant in the absence of ATRX or DAXX. Indeed, fork degradation in ATRX-null cells could be attenuated by treatment with the MRE11 inhibitor mirin, or exacerbated by inhibiting PARP-1 activity. Taken together, these results suggest that ATRX is required to limit replication stress during cellular proliferation, whereas upregulation of PARP-1 activity functions as a compensatory mechanism to protect stalled forks, limiting genomic damage, and facilitating late-born neuron production.
机译：神经祖细胞（NPC）的快速生长是产生六层新皮层的神经元分化的时间波的先决条件，同时也给调节染色质包装和基因组完整性的蛋白质带来沉重负担。由于染色质调节剂的突变引起的发育障碍的数量不断增加，进一步反映了这一问题。 ATRX基因突变会导致严重的智力障碍（α地中海贫血智力低下X连锁综合征（ATRX）; OMIM编号301040），其特征是小头畸形，泌尿生殖道异常和α地中海贫血。尽管ATRX蛋白是维持异染色质内重复DNA所必需的，但如何将其转化为疾病发病机理仍知之甚少，这是本研究的重点。我们证明，Atrx FoxG1Cre 前脑特异性条件敲除小鼠在神经发生过程中显示出poly（ADP-核糖）聚合酶-1（Parp-1）过度激活，并产生了较少的后期出生的Cux1和Brn2阳性神经元减少了皮层大小。此外，祖细胞中的DNA损伤，诱导的Parp-1和Atm活化均升高，并导致它们的细胞死亡水平提高。无ATRX的HeLa细胞对羟基脲诱导的复制压力同样敏感，累积DNA损伤并且增殖不良。受损的BRCA1-RAD51共定位和PARP-1过度激活表明停滞的复制叉没有得到有效的保护。 DNA纤维测定法证实，在没有ATRX或DAXX的情况下，停滞的复制叉的MRE11降解很普遍。实际上，可以通过用MRE11抑制剂米林治疗减轻ATRX无效细胞中的叉子降解，或通过抑制PARP-1活性而加剧。综上所述，这些结果表明需要ATRX来限制细胞增殖过程中的复制压力，而PARP-1活性的上调则作为一种补偿机制来保护停滞的叉子，限制基因组损伤并促进后期出生的神经元的产生。

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