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Special Issue "Molecular Mechanisms Safeguarding Genome Integrity in DNA Replication, Repair and Transcription"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Ennio Prosperi
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Guest Editor
Istituto di Genetica Molecolare “Luigi Luca Cavalli-Sforza”, Consiglio Nazionale delle Ricerche, Genome Stability Group, c/o Dept. Biology and Biotechnology, Via Ferrata 9, 27100 Pavia, Italy
Interests: DNA damage response (DDR); DNA repair and cell cycle checkpoints; p21(CDKN1A)/PCNA interaction; nucleotide excision repair/base excision repair; post-translational modifications of DNA repair factors; acetylation deficiency and human disease
Dr. Ornella Cazzalini
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Guest Editor
Immunology and Pathology Unit, Department of Molecular Medicine, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
Interests: Cancer Biology; Experimental Medicine

Special Issue Information

Dear Colleagues,

In recent years, knowledge on the cellular and molecular mechanisms underlying the maintenance of genome integrity has increased significantly through the identification of the signaling pathways and main players in the DNA damage response. Thanks to these advancements, crucial aspects of this important cell defense mechanism are currently being exploited, and new strategies to control abnormal cell proliferation and tumor formation are being developed. However, refined definitions of the processes involved in the DNA damage response, especially regarding their regulation, are needed to further this knowledge and identify new points of intervention. In particular, protein–protein interactions, as well as protein post-translation modifications are important components in unravelling the mechanisms responsible for the maintenance of genome stability. This Special Issue will focus on the latest research in the essential processes of DNA replication, repair, and transcription with the aim of advancing the knowledge of the roles of these molecular mechanisms in the DNA damage response.

Dr. Ornella Cazzalini
Dr. Ennio Prosperi
Guest Editors

Manuscript Submission Information

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Keywords

  • DNA damage and repair
  • DNA replication stress
  • transcription stress
  • genome stability
  • protein–protein interactions
  • post-translational modifications
  • phosphorylation, acetylation, ubiquitination, poly(ADP)-ribosylation

Published Papers (5 papers)

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Research

Article
Direct and Base Excision Repair-Mediated Regulation of a GC-Rich cis-Element in Response to 5-Formylcytosine and 5-Carboxycytosine
Int. J. Mol. Sci. 2021, 22(20), 11025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011025 - 13 Oct 2021
Viewed by 162
Abstract
Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely [...] Read more.
Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2′-deoxy-(5-fC/5-caC) or their BER-resistant 2′-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5′-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5′-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches. Full article
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Article
Transcriptional Stress Induces Chromatin Relocation of the Nucleotide Excision Repair Factor XPG
Int. J. Mol. Sci. 2021, 22(12), 6589; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126589 - 19 Jun 2021
Viewed by 647
Abstract
Endonuclease XPG participates in nucleotide excision repair (NER), in basal transcription, and in the processing of RNA/DNA hybrids (R-loops): the malfunction of these processes may cause genome instability. Here, we investigate the chromatin association of XPG during basal transcription and after transcriptional stress. [...] Read more.
Endonuclease XPG participates in nucleotide excision repair (NER), in basal transcription, and in the processing of RNA/DNA hybrids (R-loops): the malfunction of these processes may cause genome instability. Here, we investigate the chromatin association of XPG during basal transcription and after transcriptional stress. The inhibition of RNA polymerase II with 5,6-dichloro-l-β-D-ribofuranosyl benzimidazole (DRB), or actinomycin D (AD), and of topoisomerase I with camptothecin (CPT) resulted in an increase in chromatin-bound XPG, with concomitant relocation by forming nuclear clusters. The cotranscriptional activators p300 and CREB-binding protein (CREBBP), endowed with lysine acetyl transferase (KAT) activity, interact with and acetylate XPG. Depletion of both KATs by RNA interference, or chemical inhibition with C646, significantly reduced XPG acetylation. However, the loss of KAT activity also resulted in increased chromatin association and the relocation of XPG, indicating that these processes were induced by transcriptional stress and not by reduced acetylation. Transcription inhibitors, including C646, triggered the R-loop formation and phosphorylation of histone H2AX (γ-H2AX). Proximity ligation assay (PLA) showed that XPG colocalized with R-loops, indicating the recruitment of the protein to these structures. These results suggest that transcriptional stress-induced XPG relocation may represent recruitment to sites of R-loop processing. Full article
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Article
O-GlcNAcylation Affects the Pathway Choice of DNA Double-Strand Break Repair
Int. J. Mol. Sci. 2021, 22(11), 5715; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115715 - 27 May 2021
Viewed by 717
Abstract
Exposing cells to DNA damaging agents, such as ionizing radiation (IR) or cytotoxic chemicals, can cause DNA double-strand breaks (DSBs), which are crucial to repair to maintain genetic integrity. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a post-translational modification (PTM), which has been reported to be [...] Read more.
Exposing cells to DNA damaging agents, such as ionizing radiation (IR) or cytotoxic chemicals, can cause DNA double-strand breaks (DSBs), which are crucial to repair to maintain genetic integrity. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a post-translational modification (PTM), which has been reported to be involved in the DNA damage response (DDR) and chromatin remodeling. Here, we investigated the impact of O-GlcNAcylation on the DDR, DSB repair and chromatin status in more detail. We also applied charged particle irradiation to analyze differences of O-GlcNAcylation and its impact on DSB repair in respect of spatial dose deposition and radiation quality. Various techniques were used, such as the γH2AX foci assay, live cell microscopy and Fluorescence Lifetime Microscopy (FLIM) to detect DSB rejoining, protein accumulation and chromatin states after treating the cells with O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) inhibitors. We confirmed that O-GlcNAcylation of MDC1 is increased upon irradiation and identified additional repair factors related to Homologous Recombination (HR), CtIP and BRCA1, which were increasingly O-GlcNAcyated upon irradiation. This is consistent with our findings that the function of HR is affected by OGT inhibition. Besides, we found that OGT and OGA activity modulate chromatin compaction states, providing a potential additional level of DNA-repair regulation. Full article
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Article
Functional Roles of PARP2 in Assembling Protein–Protein Complexes Involved in Base Excision DNA Repair
Int. J. Mol. Sci. 2021, 22(9), 4679; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094679 - 28 Apr 2021
Viewed by 585
Abstract
Poly(ADP-ribose) polymerase 2 (PARP2) participates in base excision repair (BER) alongside PARP1, but its functions are still under study. Here, we characterize binding affinities of PARP2 for other BER proteins (PARP1, APE1, Polβ, and XRCC1) and oligomerization states of the homo- and hetero-associated [...] Read more.
Poly(ADP-ribose) polymerase 2 (PARP2) participates in base excision repair (BER) alongside PARP1, but its functions are still under study. Here, we characterize binding affinities of PARP2 for other BER proteins (PARP1, APE1, Polβ, and XRCC1) and oligomerization states of the homo- and hetero-associated complexes using fluorescence-based and light scattering techniques. To compare PARP2 and PARP1 in the efficiency of PAR synthesis, in the absence and presence of protein partners, the size of PARP2 PARylated in various reaction conditions was measured. Unlike PARP1, PARP2 forms more dynamic complexes with common protein partners, and their stability is effectively modulated by DNA intermediates. Apparent binding affinity constants determined for homo- and hetero-oligomerized PARP1 and PARP2 provide evidence that the major form of PARP2 at excessive PARP1 level is their heterocomplex. Autoregulation of PAR elongation at high PARP and NAD+ concentrations is stronger for PARP2 than for PARP1, and the activity of PARP2 is more effectively inhibited by XRCC1. Moreover, the activity of both PARP1 and PARP2 is suppressed upon their heteroPARylation. Taken together, our findings suggest that PARP2 can function differently in BER, promoting XRCC1-dependent repair (similarly to PARP1) or an alternative XRCC1-independent mechanism via hetero-oligomerization with PARP1. Full article
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Article
NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487
Int. J. Mol. Sci. 2021, 22(9), 4542; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094542 - 27 Apr 2021
Viewed by 932
Abstract
DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to [...] Read more.
DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway. Full article
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