SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

• Published in: eLife Vol. 9
• Main Authors: Atkins, Alisa, Xu, Michelle J, Li, Maggie, Rogers, Nathaniel P, Pryzhkova, Marina V, Jordan, Philip W
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 17.11.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Analysis; Animals; Apoptosis; Brain; Brain - embryology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromosome Segregation - physiology; Chromosome Structures - physiology; Chromosomes and Gene Expression; Developmental Biology; DNA damage; DNA repair; DNA Replication; Embryo, Mammalian; Embryonic Development; Gene Expression Regulation, Developmental; Genotype; Mice; Mice, Knockout; Mice, Transgenic; microcephaly; Mutation; neurogenesis; Neurogenesis - physiology; Neurons; SMC5/6; Stem cells; structural maintenance of chromosomes; Tumor proteins; microcephaly; mouse; DNA replication; DNA damage; developmental biology; chromosomes; neurogenesis; structural maintenance of chromosomes; SMC5/6; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.61171

Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein is conditionally knocked out (cKO) in the developing neocortex. cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. 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 tumor suppressor or DNA damage checkpoint kinase rescued cKO neurodevelopmental defects. Further assessment using 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.