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. 2012 Dec 5:2:186.
doi: 10.3389/fonc.2012.00186. eCollection 2012.

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

Koji Yoshimoto  1 , Masahiro Mizoguchi, Nobuhiro Hata, Hideki Murata, Ryusuke Hatae, Toshiyuki Amano, Akira Nakamizo, Tomio Sasaki
Affiliations

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

Koji Yoshimoto et al. Front Oncol. .

Abstract

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

Keywords: DNA repair; PARP; TMZ; chemoresistance; homologous recombination.

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Figures

FIGURE 1
FIGURE 1
Temozolomide function and activated DNA repair pathway. Temozolomide (TMZ) is chemically converted to MTIC (5-3-(methyltriazen-1-yl) imidazole-4-carboximide) at physiologic pH and degrades to a methyldiazonium cation, which transfers a methyl group to DNA. The most common site of methylation is N7-MeG (60–80%) followed by N3-MeA (10–20%) and O6-MeG (5–10%). When active MGMT is present, O6-MeG is repaired without cytotoxicity. When MGMT is inactivated or does not have the potential to completely repair O6-MeG, unrepaired O6-MeG is continuously repaired by the futile cycle of MMR, which ultimately induces cell death by provoking double-strand breaks (DSB). When MMR does not function properly, genomic instability is amplified. N7-MeG and N3-MeA is repaired by BER. If not repaired, alkylated bases cause a replication stall and collapse of the replication fork, generating single-strand breaks (SSBs), which ultimately induce DSB. It is possible that SSB and DSB repair pathways are activated and diminish the cytotoxic effects of TMZ.
FIGURE 2
FIGURE 2
Schematic illustration of DNA repair pathways and implicated proteins. Mismatch repair (MMR) functions in the repair of base substitution mutations as well as small insertions/deletions caused by replication errors. The heterodimeric complex of MSH2 and MSH6 recognizes base mismatches and single-base insertions/deletions, whereas the MSH2 and MSH6 complex (not described in this schema) detect larger insertions/deletions. These complexes recruit another heterodimeric complex made up of MLH1 and PMS2 to initiate the repair process by excision of mismatches and insertions/deletions and re-synthesis of the DNA strand. In base excision repair (BER), a damaged base is recognized by a DNA glycosylase enzyme. Of all DNA glycosylase, DNA glycosylase (MPG) [alkylpurine-DNA-N-glycosylase (APNG)] recognizes and removes alkylated bases before apurinic/apyrimidinic endonuclease 1 (APE1) recognizes the abasic sites and cleaves the 5′ end of the DNA. In the major BER pathway, as a short-patch pathway, DNA polymerase β (polyβ) excises the 3′ end of the DNA and fills the gap. Finally, the XRCC1-ligase III complex catalyzes the formation of phosphodiester bonds and completes the repair process. Poly (ADP-ribose) polymerase (PARP) recognizes single-strand breaks and initiates the repair process in an overlapping manner with BER. For DSB repair, non-homologous end-joining (NHEJ) and homologous recombination (HR) are utilized in the repair mechanism. In NHEJ, DSB are recognized by the Ku70/80 proteins, which bind and activate the protein kinase DNA-PKcs, recruiting XRCC4 and DNA ligase IV (Lig IV) to seal the gap. In HR, the MRE-11-RAD50-NBS1 (MRN) complex act as a sensor of DSB and binds to the break ends. Ataxia telangiectasia mutated (ATM) is then recruited to the sites of the breaks where ATM is phosphorylated and activates H2AX, generating phosphorylated H2AX (γ H2AX). DNA damage checkpoint protein 1 (MDC1) binds γ H2AX and the recombination process begins. Replication stress causes single-stranded DNA and induces subsequent DSB. In this case, single-stranded DNA is bound by replication protein A (RPA), which recruits ATR and ATR-interacting protein (ATRIP) to the break site. Rad17 and 9-1-1 are subsequently recruited to ATR-ATRIP, which is finally activated with the aid of DNA topoisomerase II-binding protein 1 (TOPBP1). In the process of HR, the BRCA1 complex with MDC1 has an essential role in damage detection. The subsequent BRCA1-BRCA1-partner and localizer of BRCA2 (PALB2)-BRCA2 complex is important in mediating HR. BRCA2-mediated Rad51 recruitment is crucial for HR. Rad52 is also needed for RAd51 to enable access to single-stranded DNA coated with RPA. The Fanconi anemia (FA) pathway functions during translesion DNA synthesis (TLS) in the repair of DNA interstrand cross-links (ICLs). ICLs are recognized by FANCM and the FA core complex, which monoubiquitinates FANCD2 and FANCI, thereby recruiting nucleases and other mediator proteins to facilitate the repair process. Recent studies have shown that the FA pathway regulates not only ICL, but also HR, possibly mediating BRCA2 and Rad51 function. The MGMT and nucleotide excision repair (NER) pathways are not described in this schema.
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References

    1. Agnihotri S., Gajadhar A. S., Ternamian C., Gorlia T., Diefes K. L., Mischel P. S., et al. (2012). Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. J. Clin. Invest. 122 253–266 - PMC - PubMed
    1. Al-Ejeh F., Kumar R., Wiegmans A., Lakhani S. R., Brown M. P., Khanna K. K. (2010). Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes. Oncogene 29 6085–6098 - PubMed
    1. Alexander B. M., Pinnell N., Wen P. Y, D’Andrea A. (2012). Targeting DNA repair and the cell cycle in glioblastoma. J. Neurooncol. 107 463–477 - PubMed
    1. Almeida K. H., Sobol R. W. (2007). A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification. DNA Repair (Amst.) 6 695–711 - PMC - PubMed
    1. Aziz K., Nowsheen S., Pantelias G., Iliakis G., Gorgoulis V. G., Georgakilas A. G. (2012). Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. Pharmacol. Ther. 133 334–350 - PubMed