A combination of direct reversion and nucleotide excision repair counters the mutagenic effects of DNA carboxymethylation

Aloisi, Claudia M. N.; Escher, Nora A; Geisen, Susanne M; Fontana, Gabriele; Yeo, Jung-Eun; Schärer, Orlando D.; Sturla, Shana J.

doi:10.1016/j.dnarep.2021.103262

Cited by 3 publications

(2 citation statements)

References 61 publications

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“…(43,44) Hence, active TC-NER could be repairing O 6 -MeG in the transcribed strand leading to the strand bias we find in our data. While it has been shown that O 6 -carboxymethylguanine as well as AP sites can be repaired by NER (45,46), no such study has been conducted for O 6 -MeG. Further studies could investigate O 6 -MeG accumulation in cells lacking proteins of TC-NER.…”

Section: Discussionmentioning

confidence: 99%

Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide

Büchel,

Mingard,

Takhaveev

et al. 2023

Preprint

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Temozolomide kills cancer cells by formingO6-methylguanine (O6-MeG), which leads to apoptosis by mismatch-repair overload, as an important basis for glioblastoma therapy. However,O6-MeG repair byO6-methylguanine-DNA methyltransferase (MGMT) strongly contributes to drug resistance. Genomic profiles ofO6-MeG may be useful for understanding howO6-MeG accumulation can be influenced by repair mechanisms, but there are no methods to map genomic locations ofO6-MeG. Here, we devised an immunoprecipitation– and polymerase-stalling-based strategy to locateO6-MeG across the whole genome at single-nucleotide resolution. We applied this strategy, termedO6-MeG-seq, to analyzeO6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines deficient in MGMT and evaluated the impact of MGMT transfection on these profiles.O6-MeG signatures from the sequencing data were highly similar to mutational signatures extracted from cancer genomes of patients previously treated with temozolomide, consistent withO6-MeG initiating mutations. Furthermore, it appears that MGMT does not preferentially repairO6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, an MGMT-independent strand bias inO6-MeG accumulation in highly expressed genes suggests alternative repair influences. These data provide high resolution insight on howO6-MeG formation and repair is impacted by genome structure and regulation.O6-MeG-seq also provides a strategy for future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

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Section: Discussionmentioning

confidence: 99%

Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide

Büchel,

Mingard,

Takhaveev

et al. 2023

Preprint

Self Cite

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“…The proposed mechanism involves NER proteins opening up the tightly packed chromatin, thereby aiding MGMT in locating and addressing the DNA adducts [217]. In a recent report, it was discovered that MGMT also collaborates with NER in processing O 6 -carboxymethylG, which has implications in colorectal cancer development and is associated with meat consumption (Figure 6) [218]. Interestingly, the expression of hMGMT in E. coli has been observed to hinder the removal of m 4 T by NER, likely due to the significantly slower removal of m 4 T by hMGMT [52].…”

Section: Mgmt and Nucleotide Excision Repair (Ner)mentioning

confidence: 99%

The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer

Fang

2024

Cancers

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O6-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT. It also explores the development of cancer therapeutic strategies that target MGMT. Finally, it discusses the intriguing crosstalk between MGMT and other DNA repair pathways.

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DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

Fahrer¹,

Christmann

2023

IJMS

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Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.

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A combination of direct reversion and nucleotide excision repair counters the mutagenic effects of DNA carboxymethylation

Cited by 3 publications

References 61 publications

Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide

Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide

The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer

DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

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A combination of direct reversion and nucleotide excision repair counters the mutagenic effects of DNA carboxymethylation

Cited by 3 publications

References 61 publications

Single-nucleotide-resolution genomic maps ofO6-methylguanine from the glioblastoma drug temozolomide

Single-nucleotide-resolution genomic maps ofO6-methylguanine from the glioblastoma drug temozolomide

The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer

DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways

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Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide

Single-nucleotide-resolution genomic maps ofO⁶-methylguanine from the glioblastoma drug temozolomide