TY - JOUR
T1 - Impact of chromatin dynamics and dna repair on genomic stability and treatment resistance in pediatric high‐grade gliomas
AU - Pinto, Lia
AU - Baidarjad, Hanane
AU - Entz‐werlé, Natacha
AU - Van Dyck, Eric
N1 - Funding Information:
Work in the E.V.D. laboratory was supported by grants from T?l?vie/Fonds National de la Recherche (F.R.S.?FNRS)/Fonds National de la Recherche du Luxembourg (FNR), the Action Lions ?Vaincre le Cancer?, a PRIDE/FNR PhD fellowship to L.P., and an AFR/FNR PhD fellowship to H.B.
Funding Information:
Funding: Work in the E.V.D. laboratory was supported by grants from Télévie/Fonds National de la Recherche (F.R.S.‐FNRS)/Fonds National de la Recherche du Luxembourg (FNR), the Action Li‐ ons “Vaincre le Cancer”, a PRIDE/FNR PhD fellowship to L.P., and an AFR/FNR PhD fellowship to H.B.
Publisher Copyright:
© 2021, MDPI. All rights reserved.
PY - 2021/11/12
Y1 - 2021/11/12
N2 - 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.
AB - 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.
KW - (peri)centromere
KW - Alternative lengthening of telomere (ALT)
KW - ATRX
KW - Chemoresistance
KW - Chromatin dynamics
KW - DAXX
KW - DNA repair
KW - Genomic instability
KW - Pediatric high‐grade gliomas
KW - Synthetic lethality
KW - Telomerase
KW - Telomere
KW - Variant H3.3 histone
UR - http://www.scopus.com/inward/record.url?scp=85119077273&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34830833
U2 - 10.3390/cancers13225678
DO - 10.3390/cancers13225678
M3 - Review article
C2 - 34830833
AN - SCOPUS:85119077273
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 22
M1 - 5678
ER -