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Table of Contents
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
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJNO.IJNO_20_21

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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 2023 Jun 1];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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