International Journal of Molecular Sciences

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4 pages, 182 KiB

Open AccessEditorial

DNA Damage, Repair, and Cancer Metabolism

by Tae-Hong Kang

Int. J. Mol. Sci. 2023, 24(22), 16430; https://doi.org/10.3390/ijms242216430 - 17 Nov 2023

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Abstract

The intricate interplay between DNA damage response (DDR) and metabolism unveils a profound insight into the fundamental mechanisms governing the maintenance of genomic integrity [...] Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

Research

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13 pages, 2454 KiB

Open AccessArticle

Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway

by Jeong-Min Park, Huimin Zhang, Litong Nie, Chao Wang, Min Huang, Xu Feng, Mengfan Tang, Zhen Chen, Yun Xiong, Namsoo Lee, Siting Li, Ling Yin, Traver Hart and Junjie Chen

Int. J. Mol. Sci. 2023, 24(7), 6545; https://doi.org/10.3390/ijms24076545 - 31 Mar 2023

Cited by 2 | Viewed by 2274

Abstract

Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides [...] Read more.

Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5′-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1–168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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13 pages, 1799 KiB

Open AccessArticle

Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells

by Mina Yeom, Jin-Kyung Hong, Joo-Ho Shin, Yunjong Lee, Frederick Peter Guengerich and Jeong-Yun Choi

Int. J. Mol. Sci. 2023, 24(6), 5198; https://doi.org/10.3390/ijms24065198 - 8 Mar 2023

Viewed by 1790

Abstract

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced cis-syn cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and [...] Read more.

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced cis-syn cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and cisplatin sensitivity, but the functional impacts of its germline variants remain unclear. We evaluated the functional properties of eight human POLH germline in silico-predicted deleterious missense variants, using biochemical and cell-based assays. In enzymatic assays, utilizing recombinant pol η (residues 1—432) proteins, the C34W, I147N, and R167Q variants showed 4- to 14-fold and 3- to 5-fold decreases in specificity constants (k_cat/K_m) for dATP insertion opposite the 3’-T and 5′-T of a CTD, respectively, compared to the wild-type, while the other variants displayed 2- to 4-fold increases. A CRISPR/Cas9-mediated POLH knockout increased the sensitivity of human embryonic kidney 293 cells to UV and cisplatin, which was fully reversed by ectopic expression of wild-type pol η, but not by that of an inactive (D115A/E116A) or either of two XPV-pathogenic (R93P and G263V) mutants. Ectopic expression of the C34W, I147N, and R167Q variants, unlike the other variants, did not rescue the UV- and cisplatin-sensitivity in POLH-knockout cells. Our results indicate that the C34W, I147N, and R167Q variants—substantially reduced in TLS activity—failed to rescue the UV- and cisplatin-sensitive phenotype of POLH-deficient cells, which also raises the possibility that such hypoactive germline POLH variants may increase the individual susceptibility to UV irradiation and cisplatin chemotherapy. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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14 pages, 1758 KiB

Open AccessArticle

Promoter Methylation of Cancer Stem Cell Surface Markers as an Epigenetic Biomarker for Prognosis of Oral Squamous Cell Carcinoma

by Yu Kyeong Han, Ha Young Park, Sae-Gwang Park, Jae Joon Hwang, Hae Ryoun Park and Joo Mi Yi

Int. J. Mol. Sci. 2022, 23(23), 14624; https://doi.org/10.3390/ijms232314624 - 23 Nov 2022

Cited by 4 | Viewed by 1601

Abstract

Growing evidence suggests that genetic and epigenetic factors, including environmental factors, contribute to the development of oral squamous cell carcinoma (OSCC). Here, we investigated the transcriptional silencing of the CD24, CD44, CD133, and CD147 genes, which are well-known cancer stem [...] Read more.

Growing evidence suggests that genetic and epigenetic factors, including environmental factors, contribute to the development of oral squamous cell carcinoma (OSCC). Here, we investigated the transcriptional silencing of the CD24, CD44, CD133, and CD147 genes, which are well-known cancer stem cell surface markers in various cancer types, including OSCC. We first examined the correlation between the transcriptional expression level and reactivation by 5-aza-2′-deoxycytidine (5-aza-dC) and the promoter methylation levels of the four genes in several OSCC cell lines. We observed promoter hypermethylation for the CD24, CD133, and CD147 genes at 70%, 75%, and 70%, respectively, in OSCC cell lines compared to normal oral mucosa tissues (<53%), indicating that this methylation pattern is cancer-specific, which was confirmed by bisulfite sequencing analysis. More specifically, the expression and methylation profiles of CD133 and CD147 extracted from The Cancer Genome Atlas (TCGA) database were negatively correlated, supporting their epigenetic regulation in primary OSCC tumors. The methylation status of CD133 and CD147 was associated with poor survival in patients with OSCC using the TCGA database. Our findings provide additional insight into the abnormal DNA methylation of CD133 and that CD147 could be used for the diagnosis and therapeutic treatment of patients with OSCC. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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Review

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16 pages, 1961 KiB

Open AccessReview

Unraveling DNA Repair Processes In Vivo: Insights from Zebrafish Studies

by Unbeom Shin and Yoonsung Lee

Int. J. Mol. Sci. 2023, 24(17), 13120; https://doi.org/10.3390/ijms241713120 - 23 Aug 2023

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Abstract

The critical role of the DNA repair system in preserving the health and survival of living organisms is widely recognized as dysfunction within this system can result in a broad range of severe conditions, including neurodegenerative diseases, blood disorders, infertility, and cancer. Despite [...] Read more.

The critical role of the DNA repair system in preserving the health and survival of living organisms is widely recognized as dysfunction within this system can result in a broad range of severe conditions, including neurodegenerative diseases, blood disorders, infertility, and cancer. Despite comprehensive research on the molecular and cellular mechanisms of DNA repair pathways, there remains a significant knowledge gap concerning these processes at an organismal level. The teleost zebrafish has emerged as a powerful model organism for investigating these intricate DNA repair mechanisms. Their utility arises from a combination of their well-characterized genomic information, the ability to visualize specific phenotype outcomes in distinct cells and tissues, and the availability of diverse genetic experimental approaches. In this review, we provide an in-depth overview of recent advancements in our understanding of the in vivo roles of DNA repair pathways. We cover a variety of critical biological processes including neurogenesis, hematopoiesis, germ cell development, tumorigenesis, and aging, with a specific emphasis on findings obtained from the use of zebrafish as a model system. Our comprehensive review highlights the importance of zebrafish in enhancing our understanding of the functions of DNA repair systems at the organismal level and paves the way for future investigations in this field. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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33 pages, 2010 KiB

Open AccessReview

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism

by Seo-Young Koo, Eun-Ji Park, Hyun-Ji Noh, Su-Mi Jo, Bo-Kyoung Ko, Hyun-Jin Shin and Chang-Woo Lee

Int. J. Mol. Sci. 2023, 24(9), 8441; https://doi.org/10.3390/ijms24098441 - 8 May 2023

Cited by 9 | Viewed by 3916

Abstract

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the [...] Read more.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin–proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/C^CDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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15 pages, 13117 KiB

Open AccessReview

Clinical and Mechanistic Implications of R-Loops in Human Leukemias

by Seo-Yun Lee, Kyle M. Miller and Jae-Jin Kim

Int. J. Mol. Sci. 2023, 24(6), 5966; https://doi.org/10.3390/ijms24065966 - 22 Mar 2023

Cited by 4 | Viewed by 2615

Abstract

Genetic mutations or environmental agents are major contributors to leukemia and are associated with genomic instability. R-loops are three-stranded nucleic acid structures consisting of an RNA–DNA hybrid and a non-template single-stranded DNA. These structures regulate various cellular processes, including transcription, replication, and DSB [...] Read more.

Genetic mutations or environmental agents are major contributors to leukemia and are associated with genomic instability. R-loops are three-stranded nucleic acid structures consisting of an RNA–DNA hybrid and a non-template single-stranded DNA. These structures regulate various cellular processes, including transcription, replication, and DSB repair. However, unregulated R-loop formation can cause DNA damage and genomic instability, which are potential drivers of cancer including leukemia. In this review, we discuss the current understanding of aberrant R-loop formation and how it influences genomic instability and leukemia development. We also consider the possibility of R-loops as therapeutic targets for cancer treatment. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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19 pages, 1354 KiB

Open AccessReview

DNA Damage and Its Role in Cancer Therapeutics

by Jaeyoung Moon, Ichiwa Kitty, Kusuma Renata, Sisi Qin, Fei Zhao and Wootae Kim

Int. J. Mol. Sci. 2023, 24(5), 4741; https://doi.org/10.3390/ijms24054741 - 1 Mar 2023

Cited by 15 | Viewed by 11372

Abstract

DNA damage is a double-edged sword in cancer cells. On the one hand, DNA damage exacerbates gene mutation frequency and cancer risk. Mutations in key DNA repair genes, such as breast cancer 1 (BRCA1) and/or breast cancer 2 (BRCA2), [...] Read more.

DNA damage is a double-edged sword in cancer cells. On the one hand, DNA damage exacerbates gene mutation frequency and cancer risk. Mutations in key DNA repair genes, such as breast cancer 1 (BRCA1) and/or breast cancer 2 (BRCA2), induce genomic instability and promote tumorigenesis. On the other hand, the induction of DNA damage using chemical reagents or radiation kills cancer cells effectively. Cancer-burdening mutations in key DNA repair-related genes imply relatively high sensitivity to chemotherapy or radiotherapy because of reduced DNA repair efficiency. Therefore, designing specific inhibitors targeting key enzymes in the DNA repair pathway is an effective way to induce synthetic lethality with chemotherapy or radiotherapy in cancer therapeutics. This study reviews the general pathways involved in DNA repair in cancer cells and the potential proteins that could be targeted for cancer therapeutics. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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16 pages, 1940 KiB

Open AccessReview

Gamma-Aminobutyric Acid Signaling in Damage Response, Metabolism, and Disease

by Kimyeong Kim and Haejin Yoon

Int. J. Mol. Sci. 2023, 24(5), 4584; https://doi.org/10.3390/ijms24054584 - 26 Feb 2023

Cited by 11 | Viewed by 8774

Abstract

Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we [...] Read more.

Gamma-aminobutyric acid (GABA) plays a crucial role in signal transduction and can function as a neurotransmitter. Although many studies have been conducted on GABA in brain biology, the cellular function and physiological relevance of GABA in other metabolic organs remain unclear. Here, we will discuss recent advances in understanding GABA metabolism with a focus on its biosynthesis and cellular functions in other organs. The mechanisms of GABA in liver biology and disease have revealed new ways to link the biosynthesis of GABA to its cellular function. By reviewing what is known about the distinct effects of GABA and GABA-mediated metabolites in physiological pathways, we provide a framework for understanding newly identified targets regulating the damage response, with implications for ameliorating metabolic diseases. With this review, we suggest that further research is necessary to develop GABA’s beneficial and toxic effects on metabolic disease progression. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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12 pages, 929 KiB

Open AccessReview

DNA Damage and Repair in Eye Diseases

by Joanna Sohn, Sang-Eun Lee and Eun-Yong Shim

Int. J. Mol. Sci. 2023, 24(4), 3916; https://doi.org/10.3390/ijms24043916 - 15 Feb 2023

Cited by 3 | Viewed by 3299

Abstract

Vision is vital for daily activities, and yet the most common eye diseases—cataracts, DR, ARMD, and glaucoma—lead to blindness in aging eyes. Cataract surgery is one of the most frequently performed surgeries, and the outcome is typically excellent if there is no concomitant [...] Read more.

Vision is vital for daily activities, and yet the most common eye diseases—cataracts, DR, ARMD, and glaucoma—lead to blindness in aging eyes. Cataract surgery is one of the most frequently performed surgeries, and the outcome is typically excellent if there is no concomitant pathology present in the visual pathway. In contrast, patients with DR, ARMD and glaucoma often develop significant visual impairment. These often-multifactorial eye problems can have genetic and hereditary components, with recent data supporting the role of DNA damage and repair as significant pathogenic factors. In this article, we discuss the role of DNA damage and the repair deficit in the development of DR, ARMD and glaucoma. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

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