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

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.

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

“…Importantly, both dKO-N and dKO-E were characterized by an abundance of reporter-expressing cells ( Fig. S1J ), indicating that loss of H3.3 did not cause widespread cell loss, unlike some models of chromatin dysregulation (45, 46). This finding was consistent with immunostaining for cleaved caspase 3 (CC3), a marker of apoptosis, and phospho-(p)KAP1 (TRIM28), a marker of DNA double-strand breaks ( Fig.…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…The INO80 subfamily is known for its role in histone variant exchange of canonical H2A or H3 histone variants, which is assisted by editing remodelers such as Swr1 complex (SWR1C) [ 290 ], mammalian Snf2-related CBP activator protein (SRCAP) [ 291 ] and p400. Recently, INO80 function in NPCs has been found essential in homologous recombination (HR) DNA repair in a p53-dependent manner [ 292 ]. Loss of Ino80 in NPCs ( Neurod6 Cre/ + ; Ino80 fl/fl ) impairs these processes, causing apoptosis and microcephaly in mice [ 292 ].…”

“…Recently, INO80 function in NPCs has been found essential in homologous recombination (HR) DNA repair in a p53-dependent manner [ 292 ]. Loss of Ino80 in NPCs ( Neurod6 Cre/ + ; Ino80 fl/fl ) impairs these processes, causing apoptosis and microcephaly in mice [ 292 ]. Interestingly, Ino80 deletion in mice leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions [ 292 ].…”

“…Loss of Ino80 in NPCs ( Neurod6 Cre/ + ; Ino80 fl/fl ) impairs these processes, causing apoptosis and microcephaly in mice [ 292 ]. Interestingly, Ino80 deletion in mice leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions [ 292 ]. In correspondence with these findings, INO80 was recently identified as a candidate gene for ID and microcephaly [ 293 ].…”

Loose ends in cancer genome structure

“…The most significant association among these was with INO80, a nucleosome remodeling enzyme that has been implicated in double stranded break (DSB) motility and mitotic homologous recombination. [94][95][96][97][98][99][100] Tumors harboring somatic truncating mutations in INO80 showed a significant depletion in the burden of Type 2 and mystery loose ends relative to wild type tumors (P = 7.18 × 10 −7 , RR = 0.082). We found a similar depletion (P = 2.13 × 10 −3 , RR = 0.647) in tumors with truncating mutations of ARID1A, a major component of the SWI/SNF nucleosome remodeling complex.…”