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

Jason M Keil,Kenneth Y Kwan,Alice Sorel,Daniel Z Doyle,Yaman Qalieh,Nitesh Mohan,Mandy M Lam,Lei Shi,Owen H Funk,Adel Qalieh

doi:10.1038/s41467-020-17551-4

Jason M Keil, Kenneth Y Kwan + Show 8 more

Open Access

https://doi.org/10.1038/s41467-020-17551-4

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Journal: Nature Communications	Publication Date: Jul 31, 2020
Citations: 22	License type: open-access

Affiliation: University of Michigan–Ann Arbor

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.

Highlights

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs)
We find that conditional deletion of Ino[80] from embryonic cortical NPCs leads to accumulation of unrepaired double-strand break (DSB), which trigger p53 target activation, robust apoptotic responses, and microcephaly
Using an in vivo assay for DSB repair pathway choice, we find that Ino[80] is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino[80] function in YY1associated transcriptional regulation

Summary

Introduction

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Sensitivity to loss of Ino80-mediated HR is dependent on NPC division mode: Ino[80] 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 Brca[2]. Disruption of chromatin regulators may contribute to neurodevelopmental disorders by impairing DNA repair in dividing NPCs, which could trigger DNA-damage response or lead to brain somatic mutations. Ino[80] plays mechanistically dissociable roles in chromatin-mediated gene regulation and DNA repair in corticogenesis, and distinct modes of NPC division have divergent requirements for HR

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