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

被引:19
|
作者
Keil, Jason M. [1 ,2 ,3 ]
Doyle, Daniel Z. [1 ,2 ,4 ]
Qalieh, Adel [1 ,2 ]
Lam, Mandy M. [1 ,2 ]
Funk, Owen H. [1 ,2 ]
Qalieh, Yaman [1 ,2 ]
Shi, Lei [1 ,2 ]
Mohan, Nitesh [1 ,2 ]
Sorel, Alice [1 ,2 ]
Kwan, Kenneth Y. [1 ,2 ,4 ]
机构
[1] Univ Michigan, Michigan Neurosci Inst MNI, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Med Scientist Training Program, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Neurosci Grad Program, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
COMPLEX; DAMAGE; GENES; BRCA2; CELLS; NEUROGENESIS; NEURONS; CRE; P53; IDENTIFICATION;
D O I
10.1038/s41467-020-17551-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Chromatin mediates transcription and DNA repair. Here, the authors show distinct roles of chromatin remodeler INO80 in expression of YY1-regulated genes and repair of DNA breaks by homologous recombination, a DNA repair pathway important for symmetrically-dividing neural progenitors.
引用
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页数:15
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