Symmetric neural progenitor divisions require chromatin-mediated homologous recombination DNA repair by Ino80

Jason M. Keil, Daniel Z. Doyle, Adel Qalieh, Mandy M. Lam, Owen H. Funk, Yaman Qalieh, Lei Shi, Nitesh Mohan, Alice Sorel and Kenneth Y. Kwan ()
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Jason M. Keil: University of Michigan
Daniel Z. Doyle: University of Michigan
Adel Qalieh: University of Michigan
Mandy M. Lam: University of Michigan
Owen H. Funk: University of Michigan
Yaman Qalieh: University of Michigan
Lei Shi: University of Michigan
Nitesh Mohan: University of Michigan
Alice Sorel: University of Michigan
Kenneth Y. Kwan: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler Ino80 in chromatin-mediated transcriptional regulation and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break (DSB) repair, triggering p53-dependent apoptosis and microcephaly. Using an in vivo DSB repair pathway assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of Ino80-mediated HR is dependent on NPC division mode: Ino80 deletion leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. This division mode dependence is phenocopied following conditional deletion of HR gene Brca2. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair.

Date: 2020
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DOI: 10.1038/s41467-020-17551-4

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