Yb1 Is Critical For Medulloblastoma Tumor Maintenance And Dna Repair Following Therapeutic Intervention

Abstract Medulloblastoma (MB) is the most common pediatric central nervous system malignancy. Although the current standard of care leads to ~70% patient survival, the therapies are highly toxic, leading to life-long side effects, and recurrence due to therapeutic resistance is fatal. We sought to investigate mediators of radiation response in mouse models for the Sonic hedgehog (SHH) subgroup MB as well as human cell lines. We previously identified Y-box binding protein 1 (YB1) as a downstream effector of YAP-mediated MB radiation resistance. YB1 is a crucial, yet understudied, protein highly expressed across all 4 subgroups of MB. Through its DNA- and RNA-binding cold shock domain, YB1 mediates both transcriptional and translational changes important for tumor maintenance and therapeutic response. We show that following ionizing radiation, YB1 mediates DNA repair through PARP and that PARP inhibition abrogates YB1-mediated DNA repair in cells overexpressing YB1. Additionally, through its inhibitory effects on p53, YB1 is capable of mediating anti-apoptotic effects in response to genotoxic insult. By targeting YB1 with short hairpin RNA, we show that cells are more amenable to ionizing radiation induced double strand breaks. Additionally, we utilize RNA binding protein immunoprecipitation sequencing to investigate post transcriptional regulation of RNAs bound by YB1. We show that YB1 binds numerous transcripts critical for the identity of early cerebellar progenitor cells, the putative cell of origin for SHH subgroup tumors, in addition to transcripts important for cell cycling and migration.