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Biomolecules
Special Issues
Functional Analysis of Genes Related to DNA Damage
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Functional Analysis of Genes Related to DNA Damage

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 25 September 2026 | Viewed by 2709

Special Issue Editors

Dr. Ryan P. Barnes

E-Mail Website
Guest Editor
University of Kansas Medical Center, Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA
Interests: oxidative stress; cancer and aging; DNA damage; DNA replication and genome stability
Dr. Amy M. Whitaker

E-Mail Website
Guest Editor
Fox Chase Cancer Center, Nuclear Dynamics and Cancer Program, Cancer Epigenetics Institute, Philadelphia, PA, USA
Interests: DNA damage and repair; tumor suppressors and oncogenes; DNA secondary structures

Special Issue Information

Dear Colleagues,

Since the 1970s, it has been understood that unrepaired DNA damage can increase mutagenesis and chromosomal instability. Humans have at least five broad DNA repair pathways, in addition to DNA damage tolerance pathways, and the proteins in these pathways work together on genome maintenance. The importance of these pathways is evident from clinical observation, with their mutation resulting in diseases such as Xeroderma Pigmentosum, Lynch syndrome, Fanconi anemia, etc. Accumulating evidence over the past two decades also shows that these DNA repair proteins are involved in other nuclear transactions including cell cycle control, DNA replication, immune cell diversity, epigenetics, and genome stability.

This Special Issue is a collection of research articles and reviews that highlight recent advances in how the proteins that maintain genome integrity and function are regulated. In addition to their fundamental enzymology, we will also highlight how these factors are manipulated in the context of pathologies such as cancer, premature aging, and neurodegeneration.

Dr. Ryan P. Barnes
Dr. Amy M. Whitaker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA damage
  • DNA repair
  • genome stability
  • DNA replication stress

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Published Papers (5 papers)

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Research

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22 pages, 7374 KB  
Article
A Cisplatin-Based Prodrug Inhibits Nucleotide Excision Repair Independently of Chromatin Accessibility to Overcome Resistance
by Ya’ara Negev-Korem, Hadar Golan-Berman, Elisheva Heilbrun, Subhendu Karmakar, Yoram Soroka, Marina Frušić-Zlotkin, Ofer Chen, Hiba Hassanain, Esther Stern, Ori Wald, Dan Gibson, Ron Kohen and Sheera Adar
Biomolecules 2026, 16(4), 542; https://doi.org/10.3390/biom16040542 - 7 Apr 2026
Viewed by 374
Abstract
Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression [...] Read more.
Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcriptional regulation. Combining cisplatin with KDAC inhibitors has shown promise, often attributed to increased drug sensitivity through higher chromatin accessibility; however, this hypothesis has not been validated. Here, we synthesized a novel Pt(IV) derivative, ctc-[Pt(NH3)2(VPA)(PhB)Cl2] (cPVP), which combines cisplatin with two KDAC inhibitors, phenylbutyrate and valproic acid. Compared with cisplatin, cPVP induced significantly greater cytotoxicity, and increased DNA damage formation. High-resolution mapping of genomic cisplatin damage and repair indicated that enhanced sensitivity resulted not from altered chromatin accessibility, but from increased drug uptake and the inhibition of NER. Moreover, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, these results establish the inhibition of nucleotide excision repair, rather than enhanced damage sensitivity due to chromatin accessibility, as the primary mechanism by which KDAC-targeting cisplatin prodrugs overcome resistance to platinum-based therapies. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
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22 pages, 4869 KB  
Article
Hypomorphic Protein Expression of DNA Polymerase Beta in PolβL301R-V303R/L301R-V303R Knock-In Transgenic Mice Does Not Impact Global DNA Methylation Levels in the Midbrain
by Bryce Jacobs, Dan Ivanov, Ivana Barraza, Christopher Faulk, Carmen J. Booth, Raquel Mattos-Canedo, Lucas Tian, Kaitlyn DePietro, Alper Uzun, Wynand P. Roos, Laurie H. Sanders and Robert W. Sobol
Biomolecules 2026, 16(3), 412; https://doi.org/10.3390/biom16030412 - 11 Mar 2026
Viewed by 651
Abstract
DNA polymerase beta (Polβ) is a 39 kDa, single polypeptide enzyme that possesses both gap tailoring and nucleotidyl transferase activity and is the key polymerase involved in base excision repair (BER) and the final steps of active gene demethylation. We demonstrated that residues [...] Read more.
DNA polymerase beta (Polβ) is a 39 kDa, single polypeptide enzyme that possesses both gap tailoring and nucleotidyl transferase activity and is the key polymerase involved in base excision repair (BER) and the final steps of active gene demethylation. We demonstrated that residues in the mouse Polβ protein, L301 and V303, are critical for Polβ’s interaction with the BER scaffolding protein X-ray repair cross-complementing 1 (XRCC1), and mutation of these residues impairs Polβ’s ability to bind to XRCC1, negatively impacting BER complex assembly. We developed PolβL301R-V303R/L301R-V303R knock-in mice to explore how defects with this essential protein complex impact genome stability in the mouse. We found these mice to be viable and fertile yet exhibited a modest reduction in body weight. Here, we examined the protein and mRNA levels in tissues from wild-type (WT), heterozygous (HET), and homozygous (HOM) PolβL301R-V303R/L301R-V303R mice and the derived fibroblast cell lines. We show that HOM mice have significantly diminished Polβ protein levels, as compared to WT mice, in several tissues, yet Polβ mRNA levels were not significantly different, suggesting the decreased levels of Polβ protein could not be attributed to lower gene expression. Upon examination of Polβ stability in mouse ear fibroblasts derived from WT and HOM mice, results are consistent with human cell studies that the PolβL301R-V303R protein is unstable and undergoes proteasome-mediated degradation. Finally, we evaluated WT, and HOM, liver and brain genomic DNA samples for 5-methylcytosine/5-hydroxymethylcytosine (5mC/5hmC) levels by nanopore sequencing to investigate the impact of suppressed Polβ protein levels on active gene demethylation. As expected, we found tissue-specific trends in methylation, when comparing the brain and liver. However, we were unable to discern substantial differences in methylation levels between WT and HOM mice, suggesting that in the absence of external stressors, low Polβ levels do not impact methylation patterns. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
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16 pages, 1878 KB  
Article
Mitochondrial DNA Damage and Histological Features in Liver Tissue of Azoxymethane-Treated Apex1 Haploinsufficient Mice
by Carmen M. Pérez-Pérez, Adlin Rodríguez-Muñoz, Gerardo G. Mackenzie, Karen E. Matsukuma, María R. Castro-Achi, Sylvette Ayala-Peña and Carlos A. Torres-Ramos
Biomolecules 2025, 15(12), 1706; https://doi.org/10.3390/biom15121706 - 6 Dec 2025
Viewed by 698
Abstract
Mitochondrial dysfunction and loss of mitochondrial DNA (mtDNA) integrity are increasingly recognized as key contributors to liver diseases such as cirrhosis and hepatocellular carcinoma. However, the role of mtDNA repair in maintaining mitochondrial homeostasis during liver injury remains poorly understood. Apurinic/apyrimidinic endonuclease 1 [...] Read more.
Mitochondrial dysfunction and loss of mitochondrial DNA (mtDNA) integrity are increasingly recognized as key contributors to liver diseases such as cirrhosis and hepatocellular carcinoma. However, the role of mtDNA repair in maintaining mitochondrial homeostasis during liver injury remains poorly understood. Apurinic/apyrimidinic endonuclease 1 (APE1), encoded by the Apex1 gene, is the primary endonuclease mediating base excision repair of mtDNA. We hypothesize that APE1 is required to preserve mtDNA integrity in response to genotoxic stress in the liver. To test this, wild-type (WT) and Apex1 haploinsufficient mice (Apex1+/−) were treated with the alkylating agent azoxymethane (AOM), a carcinogen bioactivated in the liver, and tissues were collected 20 weeks after the last exposure. Apex1+/− mice exhibited a 3.2-fold increase in mtDNA lesions and a 55% reduction in mtDNA abundance, changes not observed in WT mice. Bioenergetics profiling revealed a 1.5-fold increase in the ATP5β/GAPDH ratio in WT mice and a 2.5-fold increase in Apex1+/− mice, indicating a more pronounced shift toward oxidative phosphorylation in the absence of full APE1 function. Histological analysis indicated increased nuclear inclusions and ductular proliferation in both strains, whereas fibrosis was attenuated in Apex1+/− mice. Collectively, these findings show that APE1 is essential for preserving mtDNA integrity and regulating bioenergetics and histopathological responses to alkylation-induced liver injury, highlighting its dual role in mitochondrial maintenance and modulating inflammatory outcomes. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
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Review

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38 pages, 4136 KB  
Review
Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You
by Adriana Chiaramida, Christopher B. Cummings and Thomas L. Clarke
Biomolecules 2026, 16(4), 589; https://doi.org/10.3390/biom16040589 - 15 Apr 2026
Abstract
Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and [...] Read more.
Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and contributes to a wide spectrum of human disorders, including developmental syndromes, premature aging, and multiple cancers. Here, we review how chromatin state and remodeling complexes shape detection, signaling, and resolution of DNA double-strand breaks, and we examine how their misregulation drives disease and presents opportunities for therapeutic intervention. Specifically, we discuss how post-translational modifications and ATP-dependent chromatin remodeling complexes contribute to DNA damage repair with a particular focus on DNA double-strand breaks, one of the most deleterious DNA lesions. We summarize how chromatin remodeling and histone post-translational modifications regulate DNA repair pathway choice, and how these processes are essential for safeguarding genomic integrity and preventing human disease. Finally, we discuss emerging concepts and major unanswered questions in the context of chromatin function and DNA double-strand break repair, with a focus on exploring the emerging literature on the role of chromatin compartments and topological associated domains for orchestrating DNA repair within chromatin and safeguarding genomic stability. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
16 pages, 1396 KB  
Review
Insights into Tardigrade Damage-Suppression Protein, Dsup
by Tyler J. Woodward and M. Todd Washington
Biomolecules 2026, 16(3), 455; https://doi.org/10.3390/biom16030455 - 18 Mar 2026
Viewed by 510
Abstract
Tardigrades are microscopic invertebrates capable of surviving extreme environmental conditions through unique molecular adaptations. Among the proteins implicated in their remarkable resilience is a novel protein known as damage suppressor (Dsup), a key factor in protecting cellular DNA from elevated levels of radiation. [...] Read more.
Tardigrades are microscopic invertebrates capable of surviving extreme environmental conditions through unique molecular adaptations. Among the proteins implicated in their remarkable resilience is a novel protein known as damage suppressor (Dsup), a key factor in protecting cellular DNA from elevated levels of radiation. Since its discovery, numerous studies have explored the biochemical, structural, and functional properties of Dsup. In this review, we summarize the current knowledge surrounding these properties and describe several proposed mechanisms by which Dsup may confer protection. For each proposed mechanism, we outline the foundational model, present supporting evidence, and highlight critical gaps in our understanding. Taken together, we believe that Dsup likely employs multiple complementary mechanisms to protect DNA. Finally, we discuss emerging applications of Dsup and Dsup-inspired technologies for human health. Overall, this review synthesizes our current understanding and provides a framework to guide future investigations into this remarkable protein. Full article
(This article belongs to the Special Issue Functional Analysis of Genes Related to DNA Damage)
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