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

Abstract

Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein <i>Smc5</i> is conditionally knocked out (cKO) in the developing neocortex. <i>Smc5</i> cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. <i>Smc5</i> 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 <i>Trp53</i> tumor suppressor or <i>Chek2</i> DNA damage checkpoint kinase rescued <i>Smc5</i> cKO neurodevelopmental defects. Further assessment using <i>Smc5</i> 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.