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; Kenneth Y Kwan

doi:10.1038/s41467-020-17551-4

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

Nat Commun. 2020 Jul 31;11(1):3839. doi: 10.1038/s41467-020-17551-4.

Authors

Jason M Keil^{1

2

3}, Daniel Z Doyle^{1

2

4}, Adel Qalieh^{1

2}, Mandy M Lam^{1

2}, Owen H Funk^{1

2}, Yaman Qalieh^{1

2}, Lei Shi^{1

2}, Nitesh Mohan^{1

2}, Alice Sorel^{1

2}, Kenneth Y Kwan^{5

6

7}

Affiliations

¹ Michigan Neuroscience Institute (MNI), University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, 48109, USA.
⁴ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA.
⁵ Michigan Neuroscience Institute (MNI), University of Michigan, Ann Arbor, MI, 48109, USA. [email protected].
⁶ Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA. [email protected].
⁷ Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, 48109, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATPases Associated with Diverse Cellular Activities / deficiency
ATPases Associated with Diverse Cellular Activities / genetics*
Animals
Apoptosis / genetics
BRCA2 Protein / deficiency
BRCA2 Protein / genetics*
Cell Division
Chromatin / chemistry*
Chromatin / metabolism
Chromatin Assembly and Disassembly
DNA / genetics
DNA / metabolism
DNA Breaks, Double-Stranded
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics*
Embryo, Mammalian
Gene Expression Regulation, Developmental
Mice
Mice, Transgenic
Neocortex / cytology
Neocortex / growth & development
Neocortex / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / metabolism*
Neurogenesis / genetics*
Recombinational DNA Repair*
Signal Transduction
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
YY1 Transcription Factor / genetics
YY1 Transcription Factor / metabolism

Substances

BRCA2 Protein
BRCA2 protein, mouse
Chromatin
DNA-Binding Proteins
Tumor Suppressor Protein p53
YY1 Transcription Factor
Yy1 protein, mouse
DNA
ATPases Associated with Diverse Cellular Activities
INO80 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding