Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

Simple Summary: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, due in great part to treatment resistance driven by complex DNA repair mechanisms. pHGGs have recently been divided into molecular subtypes based on mutations affecting the N-terminal tail of the histone variant H3.3 and the ATRX/DAXX histone chaperone that deposits H3.3 at repetitive heterochromatin loci that are of paramount importance to the stability of our genome. This review addresses the functions of H3.3 and ATRX/DAXX in chromatin dynamics and DNA repair, as well as the impact of mutations affecting H3.3/ATRX/DAXX on treatment resistance and how the vulnerabilities they expose could foster novel therapeutic strategies.Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy-genotoxic chemotherapy and ionizing radiation (IR)-facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs.