No 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.

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Clinical application of truly targeted therapy relies on identification of a specific molecular feature (the target) that is biologically relevant, reproducibly measurable and definably correlated with clinical benefit. Ideally the target should be crucial to the tumor's malignant phenotype. The target must be easily measurable in readily obtained clinical samples. Interruption, interference or inhibition of the target should yield a clinical response in a significant proportion of patients whose tumors express the target but in few patients whose tumors do not express the target. As such, targeted therapy offers the twin hopes of maximizing efficacy while minimizing toxicity. A critical review of the hallmarks of malignancy provides a framework for considering potential targets and novel therapeutic interventions. The hallmarks of malignancy include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis, and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionizing radiation or inhibition of estrogen receptor and HER2 growth factor signaling pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial yet therapeutically unimportant, an unlikely paradox.