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

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....

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Autores principales:	Lia Pinto, Hanane Baidarjad, Natacha Entz-Werlé, Eric Van Dyck
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	pediatric high-grade gliomas chemoresistance chromatin dynamics DNA repair genomic instability variant H3.3 histone Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/60ac7f5d32c444ff81ce52d382836c5b
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spelling	oai:doaj.org-article:60ac7f5d32c444ff81ce52d382836c5b2021-11-25T17:02:34ZImpact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas10.3390/cancers132256782072-6694https://doaj.org/article/60ac7f5d32c444ff81ce52d382836c5b2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5678https://doaj.org/toc/2072-6694Despite 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 <i>ATRX</i> 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.Lia PintoHanane BaidarjadNatacha Entz-WerléEric Van DyckMDPI AGarticlepediatric high-grade gliomaschemoresistancechromatin dynamicsDNA repairgenomic instabilityvariant H3.3 histoneNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5678, p 5678 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pediatric high-grade gliomas chemoresistance chromatin dynamics DNA repair genomic instability variant H3.3 histone Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pediatric high-grade gliomas chemoresistance chromatin dynamics DNA repair genomic instability variant H3.3 histone Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lia Pinto Hanane Baidarjad Natacha Entz-Werlé Eric Van Dyck Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
description	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 <i>ATRX</i> 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.
format	article
author	Lia Pinto Hanane Baidarjad Natacha Entz-Werlé Eric Van Dyck
author_facet	Lia Pinto Hanane Baidarjad Natacha Entz-Werlé Eric Van Dyck
author_sort	Lia Pinto
title	Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
title_short	Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
title_full	Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
title_fullStr	Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
title_full_unstemmed	Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas
title_sort	impact of chromatin dynamics and dna repair on genomic stability and treatment resistance in pediatric high-grade gliomas
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/60ac7f5d32c444ff81ce52d382836c5b
work_keys_str_mv	AT liapinto impactofchromatindynamicsanddnarepairongenomicstabilityandtreatmentresistanceinpediatrichighgradegliomas AT hananebaidarjad impactofchromatindynamicsanddnarepairongenomicstabilityandtreatmentresistanceinpediatrichighgradegliomas AT natachaentzwerle impactofchromatindynamicsanddnarepairongenomicstabilityandtreatmentresistanceinpediatrichighgradegliomas AT ericvandyck impactofchromatindynamicsanddnarepairongenomicstabilityandtreatmentresistanceinpediatrichighgradegliomas
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Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

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