Fluorescence Probes for ALKBH2 Allow the Measurement of DNA Alkylation Repair and Drug Resistance Responses

Wilson, David L.; Beharry, Andrew A.; Srivastava, Ashutosh; O’Connor, Timothy; Kool, Eric T.

doi:10.1002/ange.201807593

Cited by 12 publications

(7 citation statements)

References 29 publications

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“…e occurrence and development of cancer are often accompanied by the inactivation of one or more DRR pathways [25,26]. Current studies of DNA repair gene prognostic models focused on immediate attachment to DNA repair genes, ignoring the impingement from the TMB [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

DNA Repair and Replication-Related Gene Signature Based on Tumor Mutation Burden Reveals Prognostic and Immunotherapy Response in Gastric Cancer

Zhang

Dahai

Huangfu

et al. 2022

Journal of Oncology

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The genomic variant features (mutations, deletions, structural variants, etc.) within gastric cancer impact its evolution and immunogenicity. The tumor has developed several coping strategies to respond to these changes by DNA repair and replication (DRR). However, the intrinsic relationship between the associated DRR-related genes and gastric cancer progression remained unknown. This study selected DRR-related genes with tumor mutation burden based on the TCGA (The Cancer Genome Atlas) database of gastric cancer transcriptome and mutation data. The prognosis model of seven genes (LAMA2, CREB3L3, SELP, ABCC9, CYP1B1, CDH2, and GAMT) was constructed by a univariate and LASSO regression analysis and divided into high-risk and low-risk groups with the median risk score. Survival analysis showed that overall survival (OS) was lower in the high-risk group than that in the low-risk group. Moreover, patients with gastric cancer in the high-risk group have worse survival in different subgroups, including age, gender, histological grade, and TNM stage. The nomogram that included risk scores for DRR-related genes could accurately foresee OS of patients with gastric cancer. Interestingly, the tumor mutation burden score was higher in the low-risk group than that in the high-risk group, and the risk score for DRR-related genes was negatively correlated with tumor mutation burden in gastric cancer. Next, we further combined the risk score and tumor mutation burden to evaluate the prognosis of gastric cancer patients. The low-risk cohort had a better prognosis than the high-risk cohort in the high tumor mutation burden subgroup. The number of mutation types in the high-risk group was lower than that in the low-risk group. In the immune microenvironment of gastric cancer, more naïve B cells, memory resting CD4+ T cells, Treg cells, monocytes cells, and resting mast cells were infiltrated in the high-risk group. At last, PD-L1 and IAP expressions were negatively correlated with the risk scores; patients with gastric cancer in the low-risk group showed better immunotherapy outcomes than those in the high-risk group. Overall, the DRR-related gene signature based on tumor mutation burden is a novel biomarker for prognostic and immunotherapy response in patients with gastric cancer.

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Section: Discussionmentioning

confidence: 99%

DNA Repair and Replication-Related Gene Signature Based on Tumor Mutation Burden Reveals Prognostic and Immunotherapy Response in Gastric Cancer

Zhang

Dahai

Huangfu

et al. 2022

Journal of Oncology

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“…Examples of fluorescence strategies for quantifying and imaging DNA repair. Shown are probes of the activity of (a) UDG, (b) ALKBH, , (c) NTH1, (d) MGMT, and (e) MUTYH . The strategies make use of enzyme mechanisms that separate damage (shown in red) from the DNA and in our probes, separating quencher from fluorophore (blue/green).…”

Section: Probing Base Excision Repair With Designer Dna Basesmentioning

confidence: 99%

Chemical Tools for the Study of DNA Repair

Jun

Kool

2022

Acc. Chem. Res.

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Conspectus DNA repair enzymes continuously provide surveillance throughout our cells, protecting the enclosed DNA from the damage that is constantly arising from oxidation, alkylating species, and radiation. Members of this enzyme class are intimately linked to pathways controlling cancer and inflammation and are promising targets for diagnostics and future therapies. Their study is benefiting widely from the development of new tools and methods aimed at measuring their activities. Here, we provide an Account of our laboratory’s work on developing chemical tools to study DNA repair processes in vitro, as well as in cells and tissues, and what we have learned by applying them. We first outline early work probing how DNA repair enzymes recognize specific forms of damage by use of chemical analogs of the damage with altered shapes and H-bonding abilities. One outcome of this was the development of an unnatural DNA base that is incorporated selectively by polymerase enzymes opposite sites of missing bases (abasic sites) in DNA, a very common form of damage. We then describe strategies for design of fluorescent probes targeted to base excision repair (BER) enzymes; these were built from small synthetic DNAs incorporating fluorescent moieties to engender light-up signals as the enzymatic reaction proceeds. Examples of targets for these DNA probes include UDG, SMUG1, Fpg, OGG1, MutYH, ALKBH2, ALKBH3, MTH1, and NTH1. Several such strategies were successful and were applied both in vitro and in cellular settings; moreover, some were used to discover small-molecule modulators of specific repair enzymes. One of these is the compound SU0268, a potent OGG1 inhibitor that is under investigation in animal models for inhibiting hyperinflammatory responses. To investigate cellular nucleotide sanitation pathways, we designed a series of “two-headed” nucleotides containing a damaged DNA nucleotide at one end and ATP at the other; these were applied to studying the three human sanitation enzymes MTH1, dUTPase, and dITPase, some of which are therapeutic targets. The MTH1 probe (ARGO) was used in collaboration with oncologists to measure the enzyme in tumors as a disease marker and also to develop the first small-molecule activators of the enzyme. We proceed to discuss the development of a “universal” probe of base excision repair processes (UBER), which reacts covalently with abasic site intermediates of base excision repair. UBER probes light up in real time as the reaction occurs, enabling the observation of base excision repair as it occurs in live cells and tissues. UBER probes can also be used in efficient and simple methods for fluorescent labeling of DNA. Finally, we suggest interesting directions for the future of this field in biomedicine and human health.

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“…[39] Besides biphenylmodified DNA, other C-nucleosides equipped with aromatic residues play central roles in numerous applications including the induction of important conformational transitions, [40] relaying electron transport through duplexes, [37,38,[41][42][43] assisting the homogenous assembly of aromatic carbon layers, [44] or labeling of oligonucleotides with fluorophores. [45][46][47][48][49] However, solidphase synthesis of these analogs and biphenyl-DNA particularly is quite labor intensive and often complicated by the reduced solubility and the tendency to aggregate. Therefore, alternative methods such as enzymatic synthesis of dBph containing…”

Section: Introductionmentioning

confidence: 99%

Enzymatic synthesis of biphenyl-DNA oligonucleotides

Röthlisberger

Levi‐Acobas

Leumann

et al. 2020

Bioorganic & Medicinal Chemistry

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The incorporation of nucleotides equipped with C-glycosidic aromatic nucleobases into DNA and RNA is an alluring strategy for a number of practical applications including fluorescent labelling of oligonucleotides, expansion of the genetic alphabet for the generation of aptamers and semi-synthetic organisms, or the modulation of excess electron transfer within DNA. However, the generation of C-nucleoside containing oligonucleotides relies mainly on solidphase synthesis which is quite labor intensive and restricted to short sequences. Here, we explore the possibility of constructing biphenyl-modified DNA sequences using enzymatic synthesis. The presence of multiple biphenyl-units or biphenyl residues modified with electron donors and acceptors permits the incorporation of a single dBphMP nucleotide. Moreover, templates with multiple abasic sites enable the incorporation of up to two dBphMP nucleotides, while TdTmediated tailing reactions produce single-stranded DNA oligonucleotides with four biphenyl residues appended at the 3'-end.

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Fluorescence Probes for ALKBH2 Allow the Measurement of DNA Alkylation Repair and Drug Resistance Responses

Cited by 12 publications

References 29 publications

DNA Repair and Replication-Related Gene Signature Based on Tumor Mutation Burden Reveals Prognostic and Immunotherapy Response in Gastric Cancer

DNA Repair and Replication-Related Gene Signature Based on Tumor Mutation Burden Reveals Prognostic and Immunotherapy Response in Gastric Cancer

Chemical Tools for the Study of DNA Repair

Enzymatic synthesis of biphenyl-DNA oligonucleotides

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