SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis.
SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis.
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DOI：
10.7554/elife.61171
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发表时间：
2020-11-17
期刊：
影响因子：
7.7
通讯作者：
Jordan PW
中科院分区：
文献类型：
--
作者：
Atkins A;Xu MJ;Li M;Rogers NP;Pryzhkova MV;Jordan PW
SMC 5/6基因突变会导致发育缺陷，包括原发性小头畸形。为了模拟神经发育缺陷，我们设计了一种小鼠，其中Smc 5在发育中的新皮质中被条件性敲除（cKO）。Smc 5 cKO小鼠表现出神经发育缺陷，由于神经祖细胞（NPC）凋亡，导致皮质层神经元减少。Smc 5 cKO NPC在有丝分裂过程中形成DNA桥，并发生染色体错误分离。SMC 5/6缺失触发CHEK 2-p53 DNA损伤应答，因为同时缺失Trp 53肿瘤抑制因子或Chek 2 DNA损伤检查点激酶挽救了Smc 5 cKO神经发育缺陷。使用Smc 5 cKO和生长素诱导的降解决定子系统的进一步评估表明，SMC 5/6的缺乏导致在后期复制区域如着丝粒周围异染色质处的DNA复制应激。总之，SMC 5/6对于在进入有丝分裂之前完成DNA复制是重要的，这确保了染色体的准确分离。因此，SMC 5/6功能在生物体发育期间的高度增殖干细胞中至关重要。
Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein Smc5 is conditionally knocked out (cKO) in the developing neocortex. Smc5 cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. Smc5 cKO NPCs formed DNA bridges during mitosis and underwent chromosome missegregation. SMC5/6 depletion triggers a CHEK2-p53 DNA damage response, as concomitant deletion of the Trp53 tumor suppressor or Chek2 DNA damage checkpoint kinase rescued Smc5 cKO neurodevelopmental defects. Further assessment using Smc5 cKO and auxin-inducible degron systems demonstrated that absence of SMC5/6 leads to DNA replication stress at late-replicating regions such as pericentromeric heterochromatin. In summary, SMC5/6 is important for completion of DNA replication prior to entering mitosis, which ensures accurate chromosome segregation. Thus, SMC5/6 functions are critical in highly proliferative stem cells during organism development.