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DNA Repair, Genomic Instability and Cancer
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DNA Repair, Genomic Instability and Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (25 February 2026) | Viewed by 6559

Special Issue Editor

Prof. Dr. Karen M. Vasquez

E-Mail Website
Guest Editor
Division of Pharmacology and Toxicology, Dell Pediatric Research Institute, College of Pharmacy, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA
Interests: DNA damage and repair; genomic instability; gene targeting; DNA structure; cancer therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The maintenance of genome integrity is essential for proper cellular function and organismal survival. To protect the genome from endogenous and exogenous sources of DNA damage, cells have evolved a variety of DNA repair mechanisms. Paradoxically, in some cases, DNA repair proteins can promote genetic instability via error-prone processing, thereby contributing to the etiology and progression of diseases such as cancer. A notable example includes the processing of alternative (i.e., non-B) DNA structures, which can form repetitive DNA sequences and are abundant across genomes. In this Special Issue, we will highlight both canonical and aberrant DNA repair mechanisms, providing insights into their roles in genome integrity.

Prof. Dr. Karen M. Vasquez
Guest Editor

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Keywords

  • DNA structure
  • DNA damage
  • DNA repair
  • genomic instability
  • mutagenesis

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Published Papers (6 papers)

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Research

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14 pages, 2359 KB  
Article
Effect of DNA Methylation Modulators on UV Damage Formation and Repair 
by Kyle Jones, Rishav Rajbhandari and Wentao Li
Genes 2026, 17(4), 487; https://doi.org/10.3390/genes17040487 - 19 Apr 2026
Viewed by 310
Abstract
Background/Objectives: DNA methylation is a key epigenetic modification involved in regulating many cellular processes, including gene expression and the maintenance of genome stability. Ultraviolet (UV) radiation induces DNA damage in the form of pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] and cyclobutane pyrimidine dimers (CPDs), which [...] Read more.
Background/Objectives: DNA methylation is a key epigenetic modification involved in regulating many cellular processes, including gene expression and the maintenance of genome stability. Ultraviolet (UV) radiation induces DNA damage in the form of pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] and cyclobutane pyrimidine dimers (CPDs), which can lead to mutations if not efficiently repaired. While cytosine methylation has been implicated in influencing UV-induced DNA damage formation, the effect of DNA methylation modulators such as S-adenosyl-L-methionine (SAM) and RG108 on UV damage formation and repair remains unclear. Methods: Here, using immunoslot blot assays, we investigated the effects of SAM and RG108 on UV-induced DNA damage formation and repair in human lymphoblastoid cells. Results: We found that SAM, but not RG108, rapidly suppresses the formation of both (6-4)PP and CPD, with detectable effects within minutes of exposure. Although SAM pretreatment was associated with modestly accelerated early (6-4)PP repair, this effect was accompanied by substantially lower initial damage levels. When cells were treated with SAM or RG108 immediately after UV irradiation to ensure equivalent initial damage burden, no significant differences in repair were observed for either lesion type, demonstrating that the accelerated early (6-4)PP repair reflects reduced lesion burden rather than increased intrinsic nucleotide excision repair (NER). Global 5-methylcytosine (5mC) levels remained stable following SAM or RG108 treatment and during UV damage repair, suggesting that these effects occur independently of global alterations in DNA methylation. Conclusions: Together, our findings reveal that SAM modulates UV damage susceptibility at the level of lesion formation without altering repair, highlighting a previously unrecognized role for DNA methylation modulators in regulating genome stability. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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20 pages, 1443 KB  
Article
REV1 Loss Triggers a G2/M Cell-Cycle Arrest Through Dysregulation of Mitotic Regulators
by Brailey Buntin, Madison Guyette, Vihit Gupta, Kanayo Ikeh, Sombodhi Bhattacharya, Erica N. Lamkin, Allison Lafuze, Roxana del Rio-Guerra, Jiyong Hong, Pei Zhou and Nimrat Chatterjee
Genes 2026, 17(1), 44; https://doi.org/10.3390/genes17010044 - 31 Dec 2025
Viewed by 1699
Abstract
Background: Genomic integrity is crucial to the cellular life cycle, which involves a tightly regulated process where cells progress through specific phases to ensure that fully replicated, undamaged DNA is inherited by daughter cells. Any dysfunction in this process or unrepaired DNA damage [...] Read more.
Background: Genomic integrity is crucial to the cellular life cycle, which involves a tightly regulated process where cells progress through specific phases to ensure that fully replicated, undamaged DNA is inherited by daughter cells. Any dysfunction in this process or unrepaired DNA damage leads to cell cycle arrest and programmed cell death. Cancer cells are known to exploit these mechanisms to continue dividing. Usually, DNA damage arrests replication, allowing the DNA Damage Response (DDR) pathway to activate, which repairs the DNA or bypasses the damage to support cell survival and preserve genome integrity. For DNA damage bypass or translesion synthesis (TLS), a group of low-fidelity polymerases perform error-prone DNA synthesis opposite damaged bases, where REV1 functions as the main scaffolding protein. Previously, we reported non-TLS functions of REV1, including its role in triggering DNA damage-dependent specific DNA metabolic processes. Methods and Results: In this study, we demonstrate that REV1 plays a significant role in cell cycle progression and that its loss causes arrest at the G2/M phase in flow cytometry analysis. This unexpected phenotype includes dysregulation of G2/M regulators, such as Cyclin B1 and tubulins, in REV1-deficient cells compared to controls, as quantified by Western blot. Additionally, phosphorylation of histone H3 at serine 28 was significantly reduced in these REV1-deficient cells. These G2/M arrest features were even more pronounced in REV1-deficient cells treated with the tubulin inhibitor colchicine. Conclusions: Overall, this study reveals a previously unrecognized link between REV1 TLS polymerase inhibition and the G2/M cell cycle arrest. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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25 pages, 4126 KB  
Article
High-Mobility Group Box Protein 3 (HMGB3) Facilitates DNA Interstrand Crosslink Processing and Double-Strand Break Repair in Human Cells
by Jillian Dangerfield, Anirban Mukherjee, Wade Reh, Anna Battenhouse and Karen M. Vasquez
Genes 2025, 16(9), 1044; https://doi.org/10.3390/genes16091044 - 4 Sep 2025
Cited by 1 | Viewed by 1505
Abstract
Background/Objectives: DNA-damaging agents can contribute to genetic instability, and such agents are often used in cancer chemotherapeutic regimens due to their cytotoxicity. Thus, understanding the mechanisms involved in DNA damage processing can not only enhance our knowledge of basic DNA repair mechanisms [...] Read more.
Background/Objectives: DNA-damaging agents can contribute to genetic instability, and such agents are often used in cancer chemotherapeutic regimens due to their cytotoxicity. Thus, understanding the mechanisms involved in DNA damage processing can not only enhance our knowledge of basic DNA repair mechanisms but may also be used to develop improved chemotherapeutic strategies to treat cancer. The high-mobility group box protein 1 (HMGB1) is a known nucleotide excision repair (NER) cofactor, and its family member HMGB3 has been implicated in chemoresistance in ovarian cancer. Here, we aim to understand the potential role(s) of HMGB3 in processing DNA damage. Methods: A potential role in NER was investigated using HMGB3 knockout human cell lines in response to UV damage. Subsequently, potential roles in DNA interstrand crosslink (ICL) and DNA double-strand break (DSB) repair were investigated using mutagenesis assays, metaphase spreads, foci formation, a variety of DNA repair assays, and TagSeq analyses in human cells. Results: Interestingly, unlike HMGB1, HMGB3 does not appear to play a role in NER. We found evidence to suggest that HMGB3 is involved in the processing of both DSBs and ICLs in human cells. Conclusions: These novel results elucidate a role for HMGB3 in DNA damage repair and, surprisingly, also indicate a distinct role of HMGB3 in DNA damage repair from that of HMGB1. These findings advance our understanding of the role of HMGB3 in chemotherapeutic drug resistance and as a target for new chemotherapeutic strategies in the treatment of cancer. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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Review

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15 pages, 939 KB  
Review
The Exosome Landscape in Acute Myeloid Leukemia: From Molecular Mechanisms to Translational Frontiers
by Elizabeth Vargas-Castellanos, Dayana Barbosa-Lopéz and Jair Figueroa-Emiliani
Genes 2026, 17(3), 290; https://doi.org/10.3390/genes17030290 - 27 Feb 2026
Viewed by 629
Abstract
Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy arising from the oncogenic transformation of hematopoietic stem and progenitor cells, resulting in clonal expansion and progressive subclonal diversification. Although considerable advances have deepened our understanding of AML pathogenesis, major challenges persist, particularly [...] Read more.
Acute myeloid leukemia (AML) is a biologically heterogeneous hematologic malignancy arising from the oncogenic transformation of hematopoietic stem and progenitor cells, resulting in clonal expansion and progressive subclonal diversification. Although considerable advances have deepened our understanding of AML pathogenesis, major challenges persist, particularly regarding relapses and therapeutic resistance. In recent years, exosomes—extracellular vesicles of 30–150 nm in diameter of endosomal origin—have emerged as critical mediators of intercellular communication within the AML tumor microenvironment. These vesicles transport a diverse cargo of proteins, metabolites, and nucleic acids, including mRNA, non-coding RNA species, and DNA, which is selectively packaged during their biogenesis. Circulating exosomes have garnered attention as promising liquid biomarkers for diagnosis, prognosis, and monitoring minimal residual disease, while also representing potential therapeutic targets or delivery platforms. Nonetheless, significant knowledge gaps remain regarding the mechanisms governing exosome biogenesis, cargo selection, and the functional impact on leukemia progression and immune modulation. This review focuses on the role of exosomes in acute myeloid leukemia, with an emphasis on the molecular mechanisms underlying their involvement in pathogenesis, tumor communication, and resistance to therapies, as well as their potential as diagnostic biomarkers. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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23 pages, 2218 KB  
Review
Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease
by Magan N. Pittman, Mary Beth Nelsen, Marlo K. Thompson and Aishwarya Prakash
Genes 2026, 17(1), 82; https://doi.org/10.3390/genes17010082 - 13 Jan 2026
Cited by 1 | Viewed by 1168
Abstract
Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP [...] Read more.
Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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Other

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8 pages, 865 KB  
Brief Report
Vav-iCre-Mediated Deletion of TFAM Is Not Recoverable and Is Consistent with Embryonic Lethality
by Rituparna Ghosh, Elina Shakur and Matthew J. Yousefzadeh
Genes 2026, 17(3), 255; https://doi.org/10.3390/genes17030255 - 25 Feb 2026
Viewed by 523
Abstract
Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear [...] Read more.
Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear and mitochondrial genome instability have been shown to drive aging in the hematopoietic system, which then propagates to non-lymphoid tissues, enhancing morbidity and mortality. The loss of TFAM, a key regulator of mitochondrial DNA replication and nucleoid stability, in T cells has been shown to cause mitochondrial dysfunction, leading to premature immune aging and eventual systemic aging. We sought to investigate whether the loss of TFAM in all immune cells would have a comparable or stronger effect on both the immune system and parenchyma. To address this, we attempted to generate Vav-iCre+/−; Tfamfl/fl mice, which are deficient in TFAM in all immune cells. However, this genotype was unrecoverable as no mutant pups were born, suggesting embryonic lethality. Conversely, we generated mice lacking SIRT6, a nuclear DNA repair enzyme that also regulates mitochondrial homeostasis, in all immune cells and found them to be viable and born at expected Mendelian frequencies. Our findings demonstrate the necessity of mitochondrial genome maintenance and homeostasis repair in immunity. Full article
(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)
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