Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas.
Lia PintoHanane BaidarjadNatacha Entz-WerléEric Van DyckPublished in: Cancers (2021)
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.
Keyphrases
- dna repair
- dna damage
- high grade
- dna damage response
- low grade
- gene expression
- dna methylation
- genome wide
- transcription factor
- oxidative stress
- ejection fraction
- risk assessment
- chronic kidney disease
- end stage renal disease
- squamous cell carcinoma
- stem cells
- newly diagnosed
- combination therapy
- climate change
- locally advanced
- small molecule
- copy number
- single molecule
- cardiovascular events
- young adults
- cardiovascular disease
- coronary artery disease
- replacement therapy
- patient reported outcomes
- patient reported