Dissecting Musashi1 role in chromatin remodeling and its consequences to DNA repair and radio‐resistance

Abstract

Musashi1 (Msi1) is an evolutionarily conserved RBP with well establish roles in neuronal stem cell self‐renewal and differentiation. In the context of tumorigenesis, Msi1 has been described to be highly expressed in gliomas, medulloblastoma, lung, colon and breast cancers and linked to a poor prognosis. Its expression is required for tumor maintenance and possibly initiation. We recently established that a decrease in Msi1 expression makes glioblastoma cells more radio‐sensitive: Msi1 KD cells subjected to ionizing radiation showed reduced proliferation as evident from colony formation assays; moreover, an increase in DNA damage was observed via comet assay, γ‐H2AX expression levels and 53BP1 ionizing radiation induced foci.Msi1 has been always defined as a translation regulator. However, our recent data shows that Msi1 is often present in the nucleus of tumor samples and cell lines. Moreover, CLIP assays identified a large number of Msi1 interacting sites in intronic regions. We suggest then that Msi1 displays additional regulatory functions in the nucleus that could equally contribute to its role in tumorigenesis. Supporting this idea, among Msi1′s protein partners identified by yeast two‐hybrid and mass spectrometry are several chromatin remodeling proteins including Ino80C. The Ino80 complex has been associated with transcription factors involved in cell proliferation, differentiation and embryonic development. Moreover, Ino80 interacts directly with γH2AX during DNA double‐strand break repair. We are currently conducting experiments to explore the hypothesis that Msi1 influences radio‐resistance and DSB repair via its association with the chromatin remodeling machinery.