International Journal of Molecular Sciences

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3 pages, 201 KiB

Open AccessEditorial

DNA Damage Response (DDR) and DNA Repair

by Fiammetta Vernì

Int. J. Mol. Sci. 2022, 23(13), 7204; https://doi.org/10.3390/ijms23137204 - 29 Jun 2022

Cited by 5 | Viewed by 1599

Abstract

The first aim of cell division is to pass the genetic material, intact and unchanged, to the next generation [...] Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

Research

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10 pages, 1091 KiB

Open AccessArticle

Vitamin B6 Deficiency Promotes Loss of Heterozygosity (LOH) at the Drosophila warts (wts) Locus

by Eleonora Gnocchini, Eleonora Pilesi, Ludovica Schiano and Fiammetta Vernì

Int. J. Mol. Sci. 2022, 23(11), 6087; https://doi.org/10.3390/ijms23116087 - 29 May 2022

Cited by 4 | Viewed by 2417

Abstract

The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), is a cofactor for more than 200 enzymes involved in many metabolic pathways. Moreover, PLP has antioxidant properties and quenches the reactive oxygen species (ROS). Accordingly, PLP deficiency causes chromosome aberrations in Drosophila, [...] Read more.

The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), is a cofactor for more than 200 enzymes involved in many metabolic pathways. Moreover, PLP has antioxidant properties and quenches the reactive oxygen species (ROS). Accordingly, PLP deficiency causes chromosome aberrations in Drosophila, yeast, and human cells. In this work, we investigated whether PLP depletion can also cause loss of heterozygosity (LOH) of the tumor suppressor warts (wts) in Drosophila. LOH is usually initiated by DNA breakage in heterozygous cells for a tumor suppressor mutation and can contribute to oncogenesis inducing the loss of the wild-type allele. LOH at the wts locus results in epithelial wts homozygous tumors easily detectable on adult fly cuticle. Here, we found that PLP depletion, induced by two PLP inhibitors, promotes LOH of wts locus producing significant frequencies of wts tumors (~7% vs. 2.3%). In addition, we identified the mitotic recombination as a possible mechanism through which PLP deficiency induces LOH. Moreover, LOH of wts locus, induced by PLP inhibitors, was rescued by PLP supplementation. These data further confirm the role of PLP in genome integrity maintenance and indicate that vitamin B6 deficiency may impact on cancer also by promoting LOH. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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11 pages, 1094 KiB

Open AccessArticle

Zinc Prevents DNA Damage in Normal Cells but Shows Genotoxic and Cytotoxic Effects in Acute Myeloid Leukemia Cells

by Maria Inês Costa, Beatriz Santos Lapa, Joana Jorge, Raquel Alves, Isabel Marques Carreira, Ana Bela Sarmento-Ribeiro and Ana Cristina Gonçalves

Int. J. Mol. Sci. 2022, 23(5), 2567; https://doi.org/10.3390/ijms23052567 - 25 Feb 2022

Cited by 5 | Viewed by 2874

Abstract

Genomic instability is prevented by the DNA damage response (DDR). Micronutrients, like zinc (Zn), are cofactors of DDR proteins, and micronutrient deficiencies have been related to increased cancer risk. Acute myeloid leukemia (AML) patients commonly present Zn deficiency. Moreover, reports point to DDR [...] Read more.

Genomic instability is prevented by the DNA damage response (DDR). Micronutrients, like zinc (Zn), are cofactors of DDR proteins, and micronutrient deficiencies have been related to increased cancer risk. Acute myeloid leukemia (AML) patients commonly present Zn deficiency. Moreover, reports point to DDR defects in AML. We studied the effects of Zn in DDR modulation in AML. Cell lines of AML (HEL) and normal human lymphocytes (IMC) were cultured in standard culture, Zn depletion, and supplementation (40 μM ZnSO₄) conditions and exposed to hydrogen peroxide (H₂O₂) or ultraviolet (UV) radiation. Chromosomal damage, cell death, and nuclear division indexes (NDI) were assessed through cytokinesis-block micronucleus assay. The phosphorylated histone H2AX (yH2AX) expression was monitored at 0 h, 1 h, and 24 h after exposure. Expression of DDR genes was evaluated by quantitative real time polymerase chain reaction (qPCR). Zn supplementation increased the genotoxicity of H₂O₂ and UV radiation in AML cells, induced cytotoxic and antiproliferative effects, and led to persistent yH2AX activation. In contrast, in normal lymphocytes, supplementation decreased damage rates, while Zn depletion favored damage accumulation and impaired repair kinetics. Gene expression was not affected by Zn depletion or supplementation. Zn presented a dual role in the modulation of genome damage, preventing damage accumulation in normal cells and increasing genotoxicity and cytotoxicity in AML cells. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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16 pages, 2467 KiB

Open AccessArticle

A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase

by Zarina I. Kakhkharova, Dmitry O. Zharkov and Inga R. Grin

Int. J. Mol. Sci. 2022, 23(4), 2212; https://doi.org/10.3390/ijms23042212 - 17 Feb 2022

Cited by 7 | Viewed by 1605

Abstract

Human NEIL2 DNA glycosylase (hNEIL2) is a base excision repair protein that removes oxidative lesions from DNA. A distinctive feature of hNEIL2 is its preference for the lesions in bubbles and other non-canonical DNA structures. Although a number of associations of polymorphisms in [...] Read more.

Human NEIL2 DNA glycosylase (hNEIL2) is a base excision repair protein that removes oxidative lesions from DNA. A distinctive feature of hNEIL2 is its preference for the lesions in bubbles and other non-canonical DNA structures. Although a number of associations of polymorphisms in the hNEIL2 gene were reported, there is little data on the functionality of the encoded protein variants, as follows: only hNEIL2 R103Q was described as unaffected, and R257L, as less proficient in supporting the repair in a reconstituted system. Here, we report the biochemical characterization of two hNEIL2 variants found as polymorphisms in the general population, R103W and P304T. Arg103 is located in a long disordered segment within the N-terminal domain of hNEIL2, while Pro304 occupies a position in the β-turn of the DNA-binding zinc finger motif. Similar to the wild-type protein, both of the variants could catalyze base excision and nick DNA by β-elimination but demonstrated a lower affinity for DNA. Steady-state kinetics indicates that the P304T variant has its catalytic efficiency (in terms of k_cat/K_M) reduced ~5-fold compared with the wild-type hNEIL2, whereas the R103W enzyme is much less affected. The P304T variant was also less proficient than the wild-type, or R103W hNEIL2, in the removal of damaged bases from single-stranded and bubble-containing DNA. Overall, hNEIL2 P304T could be worthy of a detailed epidemiological analysis as a possible cancer risk modifier. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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26 pages, 41589 KiB

Open AccessArticle

The Cdc14 Phosphatase Controls Resolution of Recombination Intermediates and Crossover Formation during Meiosis

by Paula Alonso-Ramos, David Álvarez-Melo, Katerina Strouhalova, Carolina Pascual-Silva, George B. Garside, Meret Arter, Teresa Bermejo, Rokas Grigaitis, Rahel Wettstein, Marta Fernández-Díaz, Joao Matos, Marco Geymonat, Pedro A. San-Segundo and Jesús A. Carballo

Int. J. Mol. Sci. 2021, 22(18), 9811; https://doi.org/10.3390/ijms22189811 - 10 Sep 2021

Cited by 8 | Viewed by 3224

Abstract

Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases [...] Read more.

Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. The coordinated resolution of meiotic recombination intermediates is required for crossover formation, ultimately necessary for the accurate completion of both rounds of chromosome segregation. Numerous master kinases orchestrate the correct assembly and activity of the repair machinery. Although much less is known, the reversal of phosphorylation events in meiosis must also be key to coordinate the timing and functionality of repair enzymes. Cdc14 is a crucial phosphatase required for the dephosphorylation of multiple CDK1 targets in many eukaryotes. Mutations that inactivate this phosphatase lead to meiotic failure, but until now it was unknown if Cdc14 plays a direct role in meiotic recombination. Here, we show that the elimination of Cdc14 leads to severe defects in the processing and resolution of recombination intermediates, causing a drastic depletion in crossovers when other repair pathways are compromised. We also show that Cdc14 is required for the correct activity and localization of the Holliday Junction resolvase Yen1/GEN1. We reveal that Cdc14 regulates Yen1 activity from meiosis I onwards, and this function is essential for crossover resolution in the absence of other repair pathways. We also demonstrate that Cdc14 and Yen1 are required to safeguard sister chromatid segregation during the second meiotic division, a late action that is independent of the earlier role in crossover formation. Thus, this work uncovers previously undescribed functions of the evolutionary conserved Cdc14 phosphatase in the regulation of meiotic recombination. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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Review

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26 pages, 2644 KiB

Open AccessReview

Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy

by Jau-Ling Huang, Yu-Tzu Chang, Zhen-Yang Hong and Chang-Shen Lin

Int. J. Mol. Sci. 2022, 23(6), 3238; https://doi.org/10.3390/ijms23063238 - 17 Mar 2022

Cited by 16 | Viewed by 5027

Abstract

Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as [...] Read more.

Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as immune checkpoint blockade (ICB) therapy. In addition, certain altered DDR genes can be ideal therapeutic targets through adapting the mechanism of synthetic lethality. Recent studies indicate that targeting DDR can improve cancer immunotherapy by modulating the immune response mediated by cGAS-STING-interferon signaling. Investigations of the interplay of DDR-targeting and ICB therapies provide more effective treatment options for cancer patients. This review introduces the mechanisms of DDR and discusses their crucial roles in cancer therapy based on the concepts of synthetic lethality and ICB. The contemporary clinical trials of DDR-targeting and ICB therapies in breast, colorectal, and pancreatic cancers are included. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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14 pages, 2158 KiB

Open AccessReview

Plant Cytogenetics in the Micronuclei Investigation—The Past, Current Status, and Perspectives

by Jolanta Kwasniewska and Adrianna Wiktoria Bara

Int. J. Mol. Sci. 2022, 23(3), 1306; https://doi.org/10.3390/ijms23031306 - 24 Jan 2022

Cited by 11 | Viewed by 3573

Abstract

Cytogenetic approaches play an essential role as a quick evaluation of the first genetic effects after mutagenic treatment. Although labor-intensive and time-consuming, they are essential for the analyses of cytotoxic and genotoxic effects in mutagenesis and environmental monitoring. Over the years, conventional cytogenetic [...] Read more.

Cytogenetic approaches play an essential role as a quick evaluation of the first genetic effects after mutagenic treatment. Although labor-intensive and time-consuming, they are essential for the analyses of cytotoxic and genotoxic effects in mutagenesis and environmental monitoring. Over the years, conventional cytogenetic analyses were a part of routine laboratory testing in plant genotoxicity. Among the methods that are used to study genotoxicity in plants, the micronucleus test particularly represents a significant force. Currently, cytogenetic techniques go beyond the simple detection of chromosome aberrations. The intensive development of molecular biology and the significantly improved microscopic visualization and evaluation methods constituted significant support to traditional cytogenetics. Over the past years, distinct approaches have allowed an understanding the mechanisms of formation, structure, and genetic activity of the micronuclei. Although there are many studies on this topic in humans and animals, knowledge in plants is significantly limited. This article provides a comprehensive overview of the current knowledge on micronuclei characteristics in plants. We pay particular attention to how the recent contemporary achievements have influenced the understanding of micronuclei in plant cells. Together with the current progress, we present the latest applications of the micronucleus test in mutagenesis and assess the state of the environment. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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26 pages, 38650 KiB

Open AccessReview

Take a Break to Repair: A Dip in the World of Double-Strand Break Repair Mechanisms Pointing the Gaze on Archaea

by Mariarosaria De Falco and Mariarita De Felice

Int. J. Mol. Sci. 2021, 22(24), 13296; https://doi.org/10.3390/ijms222413296 - 10 Dec 2021

Cited by 5 | Viewed by 3408

Abstract

All organisms have evolved many DNA repair pathways to counteract the different types of DNA damages. The detection of DNA damage leads to distinct cellular responses that bring about cell cycle arrest and the induction of DNA repair mechanisms. In particular, DNA double-strand [...] Read more.

All organisms have evolved many DNA repair pathways to counteract the different types of DNA damages. The detection of DNA damage leads to distinct cellular responses that bring about cell cycle arrest and the induction of DNA repair mechanisms. In particular, DNA double-strand breaks (DSBs) are extremely toxic for cell survival, that is why cells use specific mechanisms of DNA repair in order to maintain genome stability. The choice among the repair pathways is mainly linked to the cell cycle phases. Indeed, if it occurs in an inappropriate cellular context, it may cause genome rearrangements, giving rise to many types of human diseases, from developmental disorders to cancer. Here, we analyze the most recent remarks about the main pathways of DSB repair with the focus on homologous recombination. A thorough knowledge in DNA repair mechanisms is pivotal for identifying the most accurate treatments in human diseases. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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25 pages, 2025 KiB

Open AccessReview

The Many Faces of Lipids in Genome Stability (and How to Unmask Them)

by María Moriel-Carretero

Int. J. Mol. Sci. 2021, 22(23), 12930; https://doi.org/10.3390/ijms222312930 - 29 Nov 2021

Cited by 7 | Viewed by 3006

Abstract

Deep efforts have been devoted to studying the fundamental mechanisms ruling genome integrity preservation. A strong focus relies on our comprehension of nucleic acid and protein interactions. Comparatively, our exploration of whether lipids contribute to genome homeostasis and, if they do, how, is [...] Read more.

Deep efforts have been devoted to studying the fundamental mechanisms ruling genome integrity preservation. A strong focus relies on our comprehension of nucleic acid and protein interactions. Comparatively, our exploration of whether lipids contribute to genome homeostasis and, if they do, how, is severely underdeveloped. This disequilibrium may be understood in historical terms, but also relates to the difficulty of applying classical lipid-related techniques to a territory such as a nucleus. The limited research in this domain translates into scarce and rarely gathered information, which with time further discourages new initiatives. In this review, the ways lipids have been demonstrated to, or very likely do, impact nuclear transactions, in general, and genome homeostasis, in particular, are explored. Moreover, a succinct yet exhaustive battery of available techniques is proposed to tackle the study of this topic while keeping in mind the feasibility and habits of “nucleus-centered” researchers. Full article

(This article belongs to the Special Issue DNA Damage Response (DDR) and DNA Repair)

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