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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 38-45

Chromatin dynamics orchestrates DNA repair mechanisms in glioblastoma


1 Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
2 Training School Complex, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission14-Jul-2021
Date of Acceptance26-Dec-2021
Date of Web Publication20-Apr-2022

Correspondence Address:
Dr. Shilpee Dutt
Tata Memorial Centre, ACTREC (Advanced Centre for Treatment, Research and Education in Cancer), Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_20_21

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  Abstract 

Glioblastoma (GBM), World Health Organization grade IV, is the most lethal and aggressive primary brain tumor. Despite maximal surgical resection, genotoxic treatment with ionizing radiation, and alkylating agent temozolomide, the median survival of the patients remains less than 12 months. Resistance and recurrence in GBM have been majorly attributed to altered DNA repair mechanisms. The DNA repair in a cell is mediated by many repair genes and proteins whose expression and recruitment are controlled epigenetically by DNA methylation and histone modifications. Understanding the mechanistic details of the interplay between DNA damage response (DDR) and epigenetics to identify potential targets has emerged as an essential therapeutic strategy for GBM. This review will summarize our current knowledge of how epigenetics modulate DDR in GBM and our understanding as to how these modifications impact therapy regimens. Finally, we will discuss the recent advances in epigenetic drugs and the scope of such drugs for future applications in treating brain tumors.

Keywords: DNA repair, epi-drugs, epigenetic modification, glioblastoma, resistance


How to cite this article:
Mahaddalkar T, Singh B, Dutt S. Chromatin dynamics orchestrates DNA repair mechanisms in glioblastoma. Int J Neurooncol 2021;4:38-45

How to cite this URL:
Mahaddalkar T, Singh B, Dutt S. Chromatin dynamics orchestrates DNA repair mechanisms in glioblastoma. Int J Neurooncol [serial online] 2021 [cited 2022 May 17];4:38-45. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/2/38/343565




  Introduction Top


Glioblastoma (GBM) is highly malignant and aggressive brain tumor originating from astrocytes. The standard treatment for GBM includes surgery, continuous doses of temozolomide (TMZ), and radiation followed by maintenance cycles of TMZ, which induces the formation of DNA lesions either in the form of DNA adducts, single-strand breaks (SSBs), or double-strand breaks (DSBs). However, despite the current aggressive treatment modalities, GBM patient survival remains poor due to therapy resistance. Many studies, including ours, attribute GBM therapy resistance to residual cells that remain after treatment and modulation of DNA damage repair mechanisms in GBM cells providing them with survival advantage and making these pathways pertinent for therapeutic targeting.[1],[2],[3],[4],[5],[6],[7] Many DNA damage response (DDR) inhibitors have entered clinical trials for treatment against GBM but failed due to the development of resistance.[7] Therefore, to develop better therapeutic strategies, it is essential to understand how GBM cells govern the pathways of DNA repair.[8] DNA damage repair is linked to epigenetic regulation such as chromatin modifications (histone modifications and DNA methylation) without altering the DNA sequence. Studies regarding the epigenome of GBM patients have revealed the importance of altered epigenetic marks in the regulation of DNA repair pathways providing another layer of potential therapeutic targets in the form of epigenetic drugs (epi-drugs) to eliminate this deadly disease. Here, we will focus on the involvement of DDR in GBM pathogenesis and the regulation of these pathways by epigenetic modifications.


  Dna damage repair pathways and glioblastoma Top


A human cell employs different repair pathways depending on the stage of division, source, and extent of damage.[9],[10] DDR is a highly dynamic process controlled by a plethora of repair proteins. Due to the different types of DNA lesions, the DNA repair proteins function in a complex interacting pathway at different steps of carcinogenesis to resolve the damage.[11] In GBM, as discussed in detail in the following, DNA adducts are repaired by the direct repair pathway and SSBs are repaired by base excision repair (BER) and mismatch repair (MMR) pathways, whereas DSBs are mainly repaired by non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways.[7]

Direct repair pathway

Direct repair pathway is mainly governed by O-6-methylguanine-DNA methyltransferase (MGMT), which removes the methyl group from the O6 site of guanine nucleotide to its cysteine residues and thus prevents mismatch errors during DNA replication and transcription, thereby maintaining genomic stability.[12] MGMT is overexpressed in GBM and has been correlated with resistance to chemotherapeutic agents.[13] Hence, in GBM, MGMT promoter hypermethylation is a crucial biomarker that influences both prognosis and clinical outcome.[12]

Conversely, if MGMT fails to remove O6 methylguanine (O6-MG) adducts, DNA polymerase during replication mismatches O6-MG with thymine leading to the activation of the MMR system.[14] MMR system consists of a protein complex comprising MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), MutL Homolog 1 (MLH1), and PMS1 Homolog 2 (PMS2) proteins, which attempt to remove mispaired thymine residues from the daughter strand. However, the persistence of O6-MG in the parent strand causes misincorporation of thymine and results in repetitive futile MMR cycles leading to DSBs and apoptotic cell death of cancer cells.[15] Similarly, GBM cells harboring MGMT methylation have O6-MG adducts, which activate repeated MMR cycles leading to apoptotic cell death.[15] Therefore, MGMT-deficient GBMs undergoing TMZ exposure pose a strong selective pressure to lose MMR function so as to extend their survival.[16] In addition to this, MSH6 mutations rise due to radiation + TMZ treatment leading to defective MMR system preventing removal of TMZ induced O6-MG, thereby imparting TMZ resistance and tumor progression in recurrent GBM.[17] This was confirmed by TCGA data analysis of 206 GBM samples that integrated mutational, DNA methylation, and clinical treatment data to reveal a link between MGMT promoter methylation and TMZ treatment that led to the creation of a selective pressure to lose MMR gene function, generating a hypermutator phenotype.[18]

Base excision repair pathway

BER is activated in GBM cells in response to radiation + TMZ treatment and involves multiple enzymes that repair damaged DNA.[19] In addition to O6-MG adducts, TMZ also induces N7 methylguanine and N3 methyladenine adducts formation, which are majorly repaired by the BER pathway.[20] Overexpression of BER proteins has been shown to cause resistance in response to radiation and TMZ in GBM. For instance, overexpression of N-methylpurine-DNA-glycosylase at the transcript level in 18 patient-derived glioma cells has been associated with GBM resistance to TMZ.[21] In another study, elevated DNA-(apurinic or apyrimidinic site) endonuclease (APEX1) levels were observed in 19 posttreatment GBM samples compared to their pretreatment counterparts. Interestingly, the authors also found a 10% change from methylated to the unmethylated status of MGMT promoter following treatment and recurrence,[22] suggesting acquired resistance is mediated by the cumulative effect of more than a single molecular alteration. Another important enzyme in the BER pathway is poly ADP-ribose polymerase 1 (PARP1), belonging to PARP family proteins that transfer ADP-ribose to target proteins. It plays an important role in SSB’s repair by forming a complex with other BER proteins like DNA ligase III, DNA polymerase beta, and the X-ray repair cross-complementing protein 1 protein.[23] Ionizing radiation has been known to cause DNA damage leading to cell cycle arrest and cellular senescence, thereby promoting progression-free survival.[24] In one of our studies, we have shown that the inhibition of PARP1 activity in combination with radiation delayed GBM recurrence both in vitro and in vivo.[3] In another study, the authors developed a TMZ-resistant cell line model that acquired MSH6 mutation and had elevated levels of PARP1 protein. Accordingly, the resistant clones were re-sensitized to therapy on receiving combination treatment of TMZ and ABT-888, commercially known as Veliparib, is a potent PARP inhibitor. Its usage has been shown to augment cytotoxicity of temozolomide and other chemotherapeutic drugs in several pre-clinical models of human tumors.[25]

Non-homologous end joining and homologous recombination repair pathways

DSBs are most lethal and repaired by two major pathways: HRR and NHEJ. A study has shown that the aprataxin and PNK-like factor (APLF), one of the DNA end processing factors in NHEJ, is elevated in GBM in response to TMZ and radiation and increases the DNA repair efficiency of NHEJ pathway rendering GBM cells resistant to therapy. The authors have shown that knocking down APLF decreased NHEJ efficiency and improved cell sensitivity to TMZ and radiation in vitro and in vivo.[26] In another study, the authors have used salinomycin to induce DNA lesions and DSBs in combination with radiotherapy, thereby inhibiting HRR pathway in resistant GBM cells both in vitro and in vivo.[27] Study from our laboratory shows inhibition of NHEJ repair pathway by NU7026 (inhibitor of key NHEJ repair pathway kinase—DNAPK) specifically eliminates residual GBM cells, thereby preventing relapse in vitro and in vivo.[2]


  Epigenetic Modulation of DNA Repair Pathways in Glioblastoma Top


Epigenetics is defined as the study of heritable phenotypic changes without altering the DNA sequence.[28] There are two major types of epigenetic modifications, namely, DNA methylation and histone modifications, that regulate gene transcription, recombination, replication, and repair. Alterations in the epigenomic landscape in GBM have been correlated with GBM tumor survival, therapy resistance, and patient survival. In the subsequent sections, we will discuss the epigenetic regulation of key DNA repair genes primarily associated with GBM at transcriptional and protein levels.


  Transcriptional Control of DNA Repair Genes Top


DNA methylation is seen in hemi-methylated 5'—Cytosine—phosphate—Guanine—3’ (CpG) dinucleotides, also called CpG islands, located in the 5’ promoter regions of 50% of all genes.[29] Epigenetic regulation of a gene involves CpG island methylation within the gene promoter by the enzymatic activity of various DNA (cytosine-5)-methyltransferases (DNMT), leading to transcriptional gene silencing. For instance, DNMT1 maintains the methylation status in the newly synthesized DNA strand, whereas DNMT3A and DNMT3B methylate de novo cytosine, under the control of DNMT3L.[30],[31],[32] Gene promoter methylation is one of the key epigenetic alterations governing carcinogenesis in GBM.[33] In a recent study conducted by isolating tumor DNA from GBM patients after treatment, promoters of various DNA repair genes including MGMT, MLH1, and Fanconi Anaemia Complementation Group F (FANCF) were found to be hypermethylated, thereby influencing clinical outcome in patients.[34] In this regard, promoter methylation of a major DNA repair gene(s) involved in glioma progression has a deleterious or beneficial effect on the tumor harboring these epigenetic alterations. The subsequent section will discuss some key DDR genes that have been studied in detail in GBM.

  • i. MGMT: Methylation status of the promoter region of MGMT gene is known to predict response to alkylating agents like TMZ treatment in glioma patients.[35] Glioma patients harboring MGMT promoter methylation correlate with a favorable prognosis and good response to TMZ in GBM compared to those harboring unmethylated MGMT promoters.[36] Studies have shown that MGMT protein expression is epigenetically regulated via methylation of CpG island in the gene promoter region, which leads to heterochromatinization, along with random nucleosome localization and rearrangement, thereby altering transcription start site and preventing binding of the transcription machinery leading to low MGMT expression, reduced DNA repair, and TMZ sensitization.


  • ii. Checkpoint kinase 1 (CHEK1) and checkpoint kinase 2 (CHEK2): CHEK1 and CHEK2 encode proteins serving as damage sensors and effectors in DDR, thereby maintaining genome integrity. In GBM, both the kinases showed reduced gene expression as compared to normal brain tissue. However, CHEK2 was most significantly downregulated. Methylation-specific polymerase chain reaction (PCR) confirmed promoter hypermethylation of CHEK2 gene, thereby inhibiting Sp1 binding for transcriptional activation. This has been associated with glioma carcinogenesis.[37] Another study showed that SAR-020106 (SAR), a Chk1 inhibitor in combination with epi-drug decitabine, can radio-sensitize GBM cells in vitro and in vivo. Hence, this multimodal treatment approach disrupts DDR, specifically HRR, leading to increased cell death in GBM cells.[38]


  • iii. Excision repair cross-complementation group 1 (ERCC1): ERCC1 is an important component of nucleotide excision repair that forms an enzyme complex with xeroderma pigmentosum complementation group F to remove DNA intrastrand crosslinks formed by various endogenous or exogenous stressors. It is also important to remove DNA interstrand crosslink via Fanconi anemia and HRR pathways. Around 38% of glioma patients have CpG island hypermethylation in the ERCC1 promoter region. Furthermore, glioma cell lines and primary human glioma samples with promoter hypermethylation of ERCC1 showed sensitivity to cisplatin and radiation.[39],[40]



  Regulation of DNA Repair Proteins by Histone Modifications Top


Chromatin structure comprises histone proteins (H1, H2A, H2B, H3, and H4), forming an integral component of chromatin machinery. Histone modifications such as methylation, phosphorylation, acetylation, and ubiquitination at the N-terminal tails of histone influence chromatin architecture and accessibility to transcription factors and DNA repair proteins, thereby exerting control over various DNA repair pathways.[41] A few well-known histone modifications include acetylation of lysine residues of histone H3 and H4 by different histone acetyltransferases and histone deacetylases (HDACs), leading to the formation of active chromatin. On the other hand, methylation of lysine 9 and 27 of histone H3 via histone methyltransferases (HKMT) is associated with condensed chromatin, while demethylation is regulated by histone lysine demethylases (KDMs).[42],[43] Furthermore, different modification patterns control the recruitment of a specific subset of factors and are also based on the type of DNA damage.[44]

Histone modifications influence DNA damage response protein recruitment to double-strand breaks

In GBM patients, those who underwent TMZ and radiotherapy, HDAC4 and HDAC6 were found to be upregulated along with sustained DNA repair and stemness phenotype, thereby leading to radioresistance and poor clinical outcome.[45] Specifically, HDAC6 interacts with MMR proteins, MSH2 and MSH6, by deacetylating these proteins, which leads to their degradation by proteasomal complex, inhibiting MMR activity. Inhibition of HDAC6 activates MMR by increasing MSH6 and MSH2 protein levels and downregulates MGMT protein expression in TMZ-resistant cells compared to TMZ-sensitive GBM cells, reflecting the oncogenic function of HDAC6 in GBM.[46] Recent studies in pediatric and adult GBM have found a high frequency of driver mutations in the Histone H3.3 protein (H3F3A) gene that encodes for H3.3 histone variant. In addition, mutations in other chromatin remodeling genes, including alpha thalassemia/mental retardation syndrome X-linked (ATRX) and Death domain-associated protein 6 (DAXX), resulted in impaired NHEJ-mediated DNA repair.[47],[48],[49] A study conducted in patient-derived GBM primary cultures showed that DNA methylation profiles in H3F3A wild-type adult GBM were similar to H3.3-mutated pediatric GBM.[50] Moreover, mutations in H3.3 lead to amino acid substitution from lysine to methionine at position 27 (K27M) or amino acid substitution from glycine to valine/arginine at position 34 (G34V/R), leading to decreased Histone H3 protein tri-methylation of lysine 27 residue (H3K27me3) deposited by enhancer of zeste homolog 2 (EZH2), an important methyltransferase that methylates H3K9 and H3K27. However, the role of H3.3 alterations in DNA repair studies remains elusive. Recent analyses have shown that EZH2-depleted GBM cells have upregulation in HRR DNA repair factors, including RAD51 (DNA repair protein). Further, in vivo studies showed that due to upregulation of RAD51-mediated DNA repair, the sensitivity of GBM cells to TMZ reduced, indicating concomitant use of inhibitors of EZH2 and HRR for GBM treatment.[51] In a screen of histone methyltransferase inhibitors that can sensitize GBM cells to radiation, Gursoy-Yuzugullu et al. found that inhibition of H4K20 methylation led to decreased recruitment of p53-binding protein 1 (53BP1) onto DSBs, whereas loss of H3K9 methylation led to the loss of ataxia-telangiectasia mutated (ATM) signaling and inhibited both HRR and NHEJ.[52] Our laboratory reported Su(var)3–9/enhancer-of-zeste/ trithorax (SET) domain and mariner transposase fusion (SETMAR), a histone lysine-N-methyltransferase, mediated increased expression of Histone H3 protein di-methylation of lysine 36 residue (H3K36me2) to facilitate KU80 (It is a DNA repair protein which is recruited to DNA double strand breaks) recruitment at radiation-induced DSBs in GBM, thereby mediating survival of residual cells.[2] Together, these studies underline the critical role histone methyltransferases play in controlling DSB repair and their potential as a novel therapeutic target to radiosensitize GBM cells. Crucial DDR proteins studied in GBM are discussed in detail in the following

  • i. ATRX: ATRX belongs to a family of chromatin remodelers called switch/sucrose non-fermenting. Together with transcription cofactor DAXX, ATRX binds to chromatin and maintain genome stability by loading histone H3.3 at telomeres and pericentromeric heterochromatin region.[53]


ATRX gene alteration is prevalent in various subtypes of glioma. Loss of ATRX protein expression caused impaired NHEJ repair and contributed to TMZ resistance. An in vivo study in the mouse GBM model showed that loss of ATRX and p53 together led to suppression of phosphorylated DNA-dependent protein kinase catalytic subunit (pDNA-PKcs) and impaired NHEJ repair.[48] ATRX loss has also been associated with a defect in RAD51–breast cancer type 1 susceptibility protein (BRCA1) co-localization, which is crucial for HRR and replication stress resolution.[54] Further, loss of ATRX protein leads to decreased H3K9me3 availability, thus failing to activate TMZ-induced ATM phosphorylation, thereby inhibiting ATM-mediated DNA repair.[55] Han et al. showed that ATRX expression is regulated by DNA demethylation mediated by Signal Transducer and Activator of Transcription 5B (STAT5b)/Tet Methylcytosine Dioxygenase 2 (TET2) complex in TMZ-resistant cells. Furthermore, ATRX stabilizes PARP1 via downregulation of Fas-associated death domain (FADD) expression by preventing H3K27me3 enrichment at FADD promoter. Thus, this study showed that ATRX/PARP1 axis contributes to TMZ resistance.[56]

  • ii. Isocitrate dehydrogenase 1 (IDH1): IDH1 is required for energy metabolism and converts isocitrate to alpha-ketoglutarate (α-KG). IDH mutants (IDH1R132H and IDH2R172H) have neomorphic activity and convert α-KG to D-2-hydroxyglutarate (2-HG), which acts as a competitive inhibitor of α-KG-dependent dioxygenases such as TET2 and Histone Lysine Demethylase subfamily 4 (KDM4), a histone demethylase.[57] IDH mutations are found in 80% of World Health Organization grade II/III gliomas and in 73% of secondary GBM.[57],[58] A recent study reported that mutant IDH1R132H, with concurrent loss of TP53 and ATRX, strengthens DDR by upregulation of BRCA1, RAD50, and RAD51, leading to efficient HRR repair. RNA-seq and Chromatin Immunoprecipitation (ChIP)-seq analysis revealed that 2-HG accumulation induced H3 hypermethylation, specifically H3K4me3, H3K36me3, and H3K27me3, by inhibiting histone demethylation and leading to epigenetic reprogramming in gliomas.[59],[60] In contrast to this, somatic mutations in ATM have imparted improved radiosensitivity in retrospectively analyzed Next-Generation Sequencing (NGS) data of six GBM and four anaplastic astrocytoma patients harboring wild-type IDH gene.[61]


  • iii. SETMAR: SETMAR is known to methylate lysine 4 and lysine 36 of histone H3.[62],[63] Studies have shown that it interacts with the components of DNA repair proteins such as Chk1 and Ligase IV and is important in the regulation of NHEJ.[45],[46] Kaur et al. showed that radiation induces SETMAR gene overexpression, leading to global euchromatization via upregulation of H3K36me2, thus increasing NHEJ repair activity in GBM cells.[2] Therefore, abrogation of SETMAR–NHEJ mechanism leads to delayed recurrence in GBM and could be used as a therapeutic target. Another chromatin modifier, SET Domain Containing 2, Histone Lysine Methyltransferase (SETD2), which is mainly involved in H3K36 trimethylation and regulation of HRR, has been shown to accumulate frameshift or point mutation in both low-grade and high-grade gliomas.[64],[65]



  Epigenetic drugs: Targeting Epigenetic Molecular Markers in Glioblastoma Top


In addition to the genetic molecular alterations, epigenetic molecular alterations provide a surplus platform for targeting tumor cells and can help in reversing therapy resistance, thereby resensitizing cancer cells to therapy.[66] Epi-drugs are chemical entities that modify DNA and chromatin structure by regulating the epigenetic proteins, thus reactivating epigenetically silenced DNA repair genes.[67] Epi-drugs act on the enzymes involved in the establishment and maintenance of epigenetic modifications and are majorly designed to target DNMTs and HDACs.[68] Variability in epigenetic alterations might be the reason for a differential therapeutic response of GBM patients. Epi-drugs in combination with DNA repair protein inhibitors [Table 1] can serve in transcriptional silencing and decreasing DNA repair protein levels, thereby controlling GBM progression.
Table 1: Epi-drugs and DNA repair protein inhibitors for GBM treatment (Epi-drugs: epigenetic drugs, GBM: glioblastoma, HDAC: histone deacetylase, ATM: ataxia-telangiectasia mutated, ATR: ataxia-telangiectasia and Rad3 related, PARP: poly ADP-ribose polymerase, IDH1: isocitrate dehydrogenase 1, LSD: lysine-specific demethylase, PRKDC: protein kinase, DNA-activated, catalytic subunit, SETD8: histone H4-lysine (20) N-methyltransferase, DOT1L: disruptor of telomeric silencing 1 (It is a Histone H3-lysine (79) N-methyltransferase), EZH2: enhancer of zeste homolog 2, G9a: lysine methyltransferase which di-methylates histone H3-lysine at position 9)

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  Conclusion Top


DNA repair and chromatin regulation have proven to be an intriguing target in cancer. GBM tumors are treated by directly inducing DNA damage by radiation or chemotherapy or indirectly by targeting DNA repair pathway proteins. However, the tumor resists the therapy, and recurrence is inevitable. This demands newer and better treatment options. As discussed in the review, epigenetic alterations play an important role in developing therapy resistance in GBM. The relationship between DNA repair and epigenetic regulation can be exploited to attain a better therapeutic response in GBM, especially in patients that develop therapy resistance. Therefore, it is imperative to understand the mechanism of how epigenomic alterations affect DNA repair pathways and to pinpoint precise target(s) specific to cancer cells. Many studies have shown the efficacy of employing epi-drugs concomitantly with radiation/chemotherapy in improving patient survival. Several epi-drugs have been studied, and a few are undergoing clinical trials. Thus, chemical inhibition of epigenetic enzymes or factors that modulate drug resistance and DNA repair is a promising avenue for therapy against GBM.

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  References Top

1.
Erasimus H, Gobin M, Niclou S, Van Dyck E. DNA repair mechanisms and their clinical impact in glioblastoma. Mutat Res Rev Mutat Res 2016;769:19-35.  Back to cited text no. 1
    
2.
Kaur E, Nair J, Ghorai A, Mishra SV, Achareker A, Ketkar M, et al. Inhibition of SETMAR-H3K36me2-NHEJ repair axis in residual disease cells prevents glioblastoma recurrence. Neuro Oncol 2020;22:1785-96.  Back to cited text no. 2
    
3.
Ghorai A, Mahaddalkar T, Thorat R, Dutt S. Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence. Cancer Lett 2020;490:44-53.  Back to cited text no. 3
    
4.
Kaur E, Rajendra J, Jadhav S, Shridhar E, Goda JS, Moiyadi A, et al. Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence. Carcinogenesis 2015;36:685-95.  Back to cited text no. 4
    
5.
Kaur E, Goda JS, Ghorai A, Salunkhe S, Shetty P, Moiyadi AV, et al. Molecular features unique to glioblastoma radiation resistant residual cells may affect patient outcome—A short report. Cell Oncol (Dordr) 2019;42:107-16.  Back to cited text no. 5
    
6.
Elmore KB, Schaff LR. DNA repair mechanisms and therapeutic targets in glioma. Curr Oncol Rep 2021;23:87.  Back to cited text no. 6
    
7.
Ferri A, Stagni V, Barilà D. Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma. Int J Mol Sci 2020;21:4910.  Back to cited text no. 7
    
8.
Dietlein F, Thelen L, Reinhardt HC. Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet 2014;30:326-39.  Back to cited text no. 8
    
9.
Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012;12:801-17.  Back to cited text no. 9
    
10.
Sulli G, Di Micco R, d’Adda di Fagagna F. Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat Rev Cancer 2012;12:709-20.  Back to cited text no. 10
    
11.
Li LY, Guan YD, Chen XS, Yang JM, Cheng Y. DNA repair pathways in cancer therapy and resistance. Front Pharmacol 2020;11:629266.  Back to cited text no. 11
    
12.
Weller M, Reifenberger G. Beyond the World Health Organization classification of central nervous system tumors 2016: What are the new developments for gliomas from a clinician’s perspective? Curr Opin Neurol 2020;33:701-6.  Back to cited text no. 12
    
13.
Gerson SL. MGMT: Its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 2004;4:296-307.  Back to cited text no. 13
    
14.
Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, et al. Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 2008;26:4189-99.  Back to cited text no. 14
    
15.
Drabløs F, Feyzi E, Aas PA, Vaagbø CB, Kavli B, Bratlie MS, et al. Alkylation damage in DNA and RNA-repair mechanisms and medical significance. DNA Repair (Amst) 2004;3:1389-407.  Back to cited text no. 15
    
16.
Casorelli I, Russo MT, Bignami M. Role of mismatch repair and MGMT in response to anticancer therapies. Anticancer Agents Med Chem 2008;8:368-80.  Back to cited text no. 16
    
17.
Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 2007;13:2038-45.  Back to cited text no. 17
    
18.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature2008;455:1061-8.  Back to cited text no. 18
    
19.
Krokan HE, Bjørås M. Base excision repair. Cold Spring Harb Perspect Biol 2013;5:a012583.  Back to cited text no. 19
    
20.
Baute J, Depicker A. Base excision repair and its role in maintaining genome stability. Crit Rev Biochem Mol Biol 2008;43:239-76.  Back to cited text no. 20
    
21.
Serrano-Heras G, Castro-Robles B, Romero-Sánchez CM, Carrión B, Barbella-Aponte R, Sandoval H, et al. Involvement of N-methylpurine DNA glycosylase in resistance to temozolomide in patient-derived glioma cells. Sci Rep 2020;10:22185.  Back to cited text no. 21
    
22.
Hudson AL, Parker NR, Khong P, Parkinson JF, Dwight T, Ikin RJ, et al. Glioblastoma recurrence correlates with increased APE1 and polarization toward an immuno-suppressive microenvironment. Front Oncol 2018;8:314.  Back to cited text no. 22
    
23.
Caldecott KW. XRCC1 protein; form and function. DNA Repair (Amst) 2019;81:102664.  Back to cited text no. 23
    
24.
Li M, You L, Xue J, Lu Y. Ionizing radiation-induced cellular senescence in normal, non-transformed cells and the involved DNA damage response: A mini review. Front Pharmacol 2018;9:522.  Back to cited text no. 24
    
25.
Yuan AL, Meode M, Tan M, Maxwell L, Bering EA, Pedersen H, et al. PARP inhibition suppresses the emergence of temozolomide resistance in a model system. J Neurooncol 2020;148:463-72.  Back to cited text no. 25
    
26.
Dong W, Li L, Teng X, Yang X, Si S, Chai J. End processing factor APLF promotes NHEJ efficiency and contributes to TMZ- and ionizing radiation-resistance in glioblastoma cells. Onco Targets Ther 2020;13:10593-605.  Back to cited text no. 26
    
27.
Lim YC, Ensbey KS, Offenhäuser C, D’souza RCJ, Cullen JK, Stringer BW, et al. Simultaneous targeting of DNA replication and homologous recombination in glioblastoma with a polyether ionophore. Neuro Oncol 2020;22:216-28.  Back to cited text no. 27
    
28.
Dupont C, Armant DR, Brenner CA. Epigenetics: Definition, mechanisms and clinical perspective. Semin Reprod Med 2009;27: 351-7.  Back to cited text no. 28
    
29.
Momparler RL, Bovenzi V. DNA methylation and cancer. J Cell Physiol 2000;183:145-54.  Back to cited text no. 29
    
30.
Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005;74:481-514.  Back to cited text no. 30
    
31.
Chen T, Li E. Structure and function of eukaryotic DNA methyltransferases. Curr Top Dev Biol 2004;60:55-89.  Back to cited text no. 31
    
32.
Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH. Dnmt3l and the establishment of maternal genomic imprints. Science 2001;294:2536-9.  Back to cited text no. 32
    
33.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 2003;33:245-54.  Back to cited text no. 33
    
34.
Kobayashi H, Ishii N, Ikeda J, Sawamura Y, Iwasaki Y. Methylation profiling of the DNA repair genes in glioblastoma multiforme and its clinical relevance. J Clin Oncol 2004;22:1572.  Back to cited text no. 34
    
35.
Yu W, Zhang L, Wei Q, Shao A. O6-methylguanine-DNA methyltransferase (MGMT): Challenges and new opportunities in glioma chemotherapy. Front Oncol 2020;9:1547.  Back to cited text no. 35
    
36.
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350-4.  Back to cited text no. 36
    
37.
Wang H, Wang S, Shen L, Chen Y, Zhang X, Zhou J, et al. Chk2 down-regulation by promoter hypermethylation in human bulk gliomas. Life Sci 2010;86:185-91.  Back to cited text no. 37
    
38.
Patties I, Kallendrusch S, Böhme L, Kendzia E, Oppermann H, Gaunitz F, et al. The chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment. J Exp Clin Cancer Res 2019;38:420.  Back to cited text no. 38
    
39.
Chen HY, Shao CJ, Chen FR, Kwan AL, Chen ZP. Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas. Int J Cancer 2010;126:1944-54.  Back to cited text no. 39
    
40.
Liu ZG, Chen HY, Cheng JJ, Chen ZP, Li XN, Xia YF. Relationship between methylation status of ERCC1 promoter and radiosensitivity in glioma cell lines. Cell Biol Int 2009;33:1111-7.  Back to cited text no. 40
    
41.
Roos WP, Krumm A. The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair. Nucleic Acids Res 2016;44:10017-30.  Back to cited text no. 41
    
42.
Turner BM. Reading signals on the nucleosome with a new nomenclature for modified histones. Nat Struct Mol Biol 2005;12: 110-2.  Back to cited text no. 42
    
43.
Kouzarides T. Chromatin modifications and their function. Cell 2007;128:693-705.  Back to cited text no. 43
    
44.
Cao LL, Shen C, Zhu WG. Histone modifications in DNA damage response. Sci China Life Sci 2016;59:257-70.  Back to cited text no. 44
    
45.
Zhang M, Xiang S, Joo HY, Wang L, Williams KA, Liu W, et al. HDAC6 deacetylates and ubiquitinates MSH2 to maintain proper levels of MutSα. Mol Cell 2014;55:31-46.  Back to cited text no. 45
    
46.
Marampon F, Megiorni F, Camero S, Crescioli C, McDowell HP, Sferra R, et al. HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. Cancer Lett 2017;397:1-11.  Back to cited text no. 46
    
47.
Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012;482:226-31.  Back to cited text no. 47
    
48.
Koschmann C, Calinescu AA, Nunez FJ, Mackay A, Fazal-Salom J, Thomas D, et al. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 2016;8:328ra28.  Back to cited text no. 48
    
49.
Gerges N, Fontebasso AM, Albrecht S, Faury D, Jabado N. Pediatric high-grade astrocytomas: A distinct neuro-oncological paradigm. Genome Med 2013;5:66.  Back to cited text no. 49
    
50.
Gallo M, Coutinho FJ, Vanner RJ, Gayden T, Mack SC, Murison A, et al. MLL5 orchestrates a cancer self-renewal state by repressing the histone variant H3.3 and globally reorganizing chromatin. Cancer Cell 2015;28:715-29.  Back to cited text no. 50
    
51.
de Vries NA, Hulsman D, Akhtar W, de Jong J, Miles DC, Blom M, et al. Prolonged Ezh2 depletion in glioblastoma causes a robust switch in cell fate resulting in tumor progression. Cell Rep 2015;10:383-97.  Back to cited text no. 51
    
52.
Gursoy-Yuzugullu O, Carman C, Serafim RB, Myronakis M, Valente V, Price BD. Epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity. Oncotarget 2017;8:24518-32.  Back to cited text no. 52
    
53.
Voon HP, Wong LH. New players in heterochromatin silencing: Histone variant H3.3 and the ATRX/DAXX chaperone. Nucleic Acids Res 2016;44:1496-501.  Back to cited text no. 53
    
54.
Huh MS, Ivanochko D, Hashem LE, Curtin M, Delorme M, Goodall E, et al. Stalled replication forks within heterochromatin require ATRX for protection. Cell Death Dis 2016;7:e2220.  Back to cited text no. 54
    
55.
Han B, Cai J, Gao W, Meng X, Gao F, Wu P, et al. Loss of ATRX suppresses ATM dependent DNA damage repair by modulating h3k9me3 to enhance temozolomide sensitivity in glioma. Cancer Lett 2018;419:280-90.  Back to cited text no. 55
    
56.
Han B, Meng X, Wu P, Li Z, Li S, Zhang Y, et al. ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma. Theranostics 2020;10:3351-65.  Back to cited text no. 56
    
57.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-73.  Back to cited text no. 57
    
58.
Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 2009;15:6002-7.  Back to cited text no. 58
    
59.
Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012;483:474-8.  Back to cited text no. 59
    
60.
Núñez FJ, Mendez FM, Kadiyala P, Alghamri MS, Savelieff MG, Garcia-Fabiani MB. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Sci Transl Med 2019;11:eaaq1427.  Back to cited text no. 60
    
61.
Kim N, Kim SH, Kang SG, Moon JH, Cho J, Suh CO, et al. ATM mutations improve radio-sensitivity in wild-type isocitrate dehydrogenase-associated high-grade glioma: Retrospective analysis using next-generation sequencing data. Radiat Oncol 2020;15:184.  Back to cited text no. 61
    
62.
Lee SH, Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, et al. The SET domain protein metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair. Proc Natl Acad Sci U S A 2005;102:18075-80.  Back to cited text no. 62
    
63.
Fnu S, Williamson EA, De Haro LP, Brenneman M, Wray J, Shaheen M, et al. Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc Natl Acad Sci U S A 2011;108:540-5.  Back to cited text no. 63
    
64.
Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F, Bachrati CZ, et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep 2014;7:2006-18.  Back to cited text no. 64
    
65.
Viaene AN, Santi M, Rosenbaum J, Li MM, Surrey LF, Nasrallah MP. SETD2 mutations in primary central nervous system tumors. Acta Neuropathol Commun 2018;6:123.  Back to cited text no. 65
    
66.
Montalvo-Casimiro M, González-Barrios R, Meraz-Rodriguez MA, Juárez-González VT, Arriaga-Canon C, Herrera LA. Epidrug repurposing: Discovering new faces of old acquaintances in cancer therapy. Front Oncol 2020;10:605386.  Back to cited text no. 66
    
67.
Salarinia R, Sahebkar A, Peyvandi M, Mirzaei HR, Jaafari MR, Riahi MM, et al. Epi-drugs and epi-miRs: Moving beyond current cancer therapies. Curr Cancer Drug Targets 2016;16:773-88.  Back to cited text no. 67
    
68.
Rodríguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med 2011;17:330-9.  Back to cited text no. 68
    
69.
Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: A north central cancer treatment group study. J Clin Oncol 2009;27:2052-8.  Back to cited text no. 69
    
70.
Galanis E, Anderson SK, Miller CR, Sarkaria JN, Jaeckle K, Buckner JC, et al; Alliance for Clinical Trials in Oncology and ABTC. Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: Results of alliance N0874/ABTC 02. Neuro Oncol 2018;20:546-56.  Back to cited text no. 70
    
71.
Watanabe S, Kuwabara Y, Suehiro S, Yamashita D, Tanaka M, Tanaka A, et al. Valproic acid reduces hair loss and improves survival in patients receiving temozolomide-based radiation therapy for high-grade glioma. Eur J Clin Pharmacol 2017;73:357-63.  Back to cited text no. 71
    
72.
Gurbani SS, Weinberg BD, Salgado E, Voloschin A, Velazquez Vega JE, Olson JJ, et al. Remarkable response of a patient with secondary glioblastoma to a histone deacetylase inhibitor. Oxf Med Case Reports 2020;2020:omaa006.  Back to cited text no. 72
    
73.
Berenguer-Daizé C, Astorgues-Xerri L, Odore E, Cayol M, Cvitkovic E, Noel K, et al. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer 2016;139:2047-55.  Back to cited text no. 73
    
74.
Sachkova A, Sperling S, Mielke D, Schatlo B, Rohde V, Ninkovic M. Combined applications of repurposed drugs and their detrimental effects on glioblastoma cells. Anticancer Res 2019;39: 207-14.  Back to cited text no. 74
    
75.
Timme CR, Rath BH, O'Neill JW, Camphausen K, Tofilon PJ. The DNA-PK inhibitor VX-984 enhances the radiosensitivity of glioblastoma cells grown in vitro and as orthotopic xenografts. Mol Cancer Ther 2018;17:1207-16.  Back to cited text no. 75
    
76.
Zenke FT, Zimmermann A, Sirrenberg C, Dahmen H, Kirkin V, Pehl U, et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Ther 2020;19:1091-101.  Back to cited text no. 76
    
77.
Munster P, Mita M, Mahipal A, Nemunaitis J, Massard C, Mikkelsen T, et al. First-in-human phase I study of A dual mtor kinase and DNA-PK inhibitor (CC-115) in advanced malignancy. Cancer Manag Res 2019;11:10463-76.  Back to cited text no. 77
    
78.
Durant ST, Zheng L, Wang Y, Chen K, Zhang L, Zhang T, et al. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv 2018;4:eaat1719.  Back to cited text no. 78
    
79.
Fròsina G, Profumo A, Marubbi D, Marcello D, Ravetti JL, Daga A. ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration. Radiat Oncol 2018;13:76.  Back to cited text no. 79
    
80.
Sun K, Mikule K, Wang Z, Poon G, Vaidyanathan A, Smith G, et al. A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. Oncotarget 2018;9:37080-96.  Back to cited text no. 80
    
81.
Gupta SK, Kizilbash SH, Carlson BL, Mladek AC, Boakye-Agyeman F, Bakken KK, et al. Delineation of MGMT hypermethylation as a biomarker for veliparib-mediated temozolomide-sensitizing therapy of glioblastoma. J Natl Cancer Inst 2016;108:djv369.  Back to cited text no. 81
    
82.
Lesueur P, Lequesne J, Grellard JM, Dugué A, Coquan E, Brachet PE, et al. Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol. BMC Cancer 2019;19:198.  Back to cited text no. 82
    



 
 
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Dna damage repai...
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