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

Abstract

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.

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

“…PNKP functions both in NHEJ and single-strand break repair pathways (Dumitrache and McKinnon, 2017) and altering both could support the synthetic growth defect observed. Since PNKP inhibition is already exploited to kill other cancers (Mereniuk et al, 2013), we suggest that it be used to sensitize pHGG cells to current radio/chemotherapeutic regimens (Pinto et al, 2021), for which there is very limited response. Moreover, the specificity towards H3.3 K27M and G34R mutant cells may limit toxicity-related side effects in future treatments and opens up the possibility of employing a similar strategy in other cancers bearing the same H3.3 mutations (Deshmukh et al, 2021).…”

“…To study whether the observed DNA repair defect is mediated by analogous perturbations of histone PTMs, we reduced H3K27me3 and H3K36me3 by inhibiting or depleting the corresponding lysine methyltransferases. The H3K27 methyltransferase Enhancer of Zeste 2 (EZH2) is endogenously inhibited in U2OS cells (Jain et al, 2019;Ragazzini et al, 2019), thus preventing further reduction of H3K27me3 upon expression of H3.3 K27M (Figure S1B and S3D). Yet, aberrant DNA repair is still observed in H3.3 K27M U2OS cells (Figure 1A-B), arguing against a contribution of H3K27me3 reduction to this repair defect.…”

“…Despite aggressive radio/chemotherapy regimens, pHGGs remain incurable and are the leading cause of cancer-related death in children (Pinto et al, 2021). The toxicity of existing therapies and the emergence of resistance hinder the efficacy of current therapeutic protocols and call for the development of alternative, targeted therapeutic strategies that exploit specific molecular features of cancer cells (Lin et al, 2022; Pinto et al, 2021). One such feature is exemplified by heterozygous, dominant point mutations in the H3F3A gene, which encodes the H3.3 histone variant.…”

Emerging nanotechnology-based therapeutics to combat multidrug-resistant cancer

“…Enhanced DNA repair pathways and chromatin dynamics are known to be associated with the development of MDR in tumor cells [ 9 , 17 , 19 ]. One recent clinical study illustrated the impact of DNA repair on genomic stability and resistance to the anticancer drug treatment of pediatric high-grade gliomas [ 20 ]. Cancer cells also become accustomed to hypoxic tissue conditions by overexpression of hypoxia-inducible factor-1α (HIF-1 α).…”

Adipocyte-mediated epigenomic instability in human T-ALL cells is cytotoxic and phenocopied by epigenetic-modifying drugs

“…This observation is consistent with its role in increasing transcription (Park et al, 2016) and our pathway analysis results of human T-ALL cells cultured in the adipocyte secretome (Figure 2B; Supplementary Figure S3). Furthermore, H3.3 histones are deposited after DNA damage (Pinto et al, 2021), and the upregulation of H3F3A may result from the increased genomic instability observed in human T-ALL cells cultured in ACM (Figure 2B; Supplementary Figure S3). In addition, we observed that the gene expression levels of H2AFX were variable among ACM-cultured human T-ALL cells; whereas the H3F3B gene was expressed at similar levels under all conditions tested.…”