Dali Zong
Burkhard Jakob
Lovisa Lundholm- 1Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- 2Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung GmbH, Darmstadt, Germany
- 3Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
- 4Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
Editorial on the Research Topic
DNA damage response in the context of chromatin
All DNA transactions, including the repair of damaged DNA, take place in the context of a highly organized yet dynamic chromatin. While studies on individual proteins have yielded important insights into the constituent components of DNA repair machineries that evolved in various organisms, it has become abundantly clear that a more complete understanding of the molecular choreography of DNA repair must take into consideration the complex interplay between repair factors and the chromatin milieu in which they operate. This Research Topic collection, termed “DNA damage response in the context of chromatin”, brings together experts at the forefront of this emerging field with a series of authoritative reviews and exciting original articles to provide a timely update on our current understandings of biology at the intersection between chromatin and DNA repair.
Local chromatin landscapes can vary profoundly within a nucleus, which may significantly influence not only the initial generation of DNA damage, but also the subsequent activation of cellular DNA damage response (DDR) pathways (Chen and Sleckman). For instance, the compact silent heterochromatin (Chansard et al.) and the transcriptionally highly active ribosomal DNA clusters confined within the nucleolus would be expected to present different physical challenges for damage detection as well as repair. In parallel, the structure of DNA lesions and their proximity to one another can pose another set of challenges. In particular, clustered damage, as produced by heavy ion radiotherapy (Danforth et al.), or enzymatically induced (Mladenova et al.), is notoriously difficult to repair and may even recruit multiple competing or mutually antagonistic repair machineries. Recent studies have identified post-translational modifications of histones, especially ubiquitylation (Kolobynina et al.), as being essential for the activation of a productive DDR that couples correct repair pathway choice (Chen and Tyler) with maintenance of epigenome integrity. In addition, certain proteins have evolved to play pivotal roles in promoting specialized DDR processes, as exemplified by Treacle, a key regulator of the nucleolar DDR (Gal et al.) that is recurrently dysregulated in human cancers (Oxe and Larsen). Finally, the global spatial architecture of chromatin (e.g., chromatin loops or chromosome territories) also influences the DDR, significantly impacting on cellular fate (Zagelbaum and Gautier, 2022).
DNA damage incurred by the human body is inherently harmful. The bulk of these lesions originate endogenously, often in the form of oxidative base damages caused by stray metabolites and polymerase errors that occasionally occur during normal DNA replication. Others are produced by acute or prolonged exposure to external sources of genotoxins, including many environmental agents (e.g., ultraviolet rays, tobacco smoke, radon, heavy metal contaminants) and a host of chemo-radiotherapeutics. Nevertheless, it should be pointed out that certain types of DNA lesions can actually be generated as part of important physiological processes, including antigen receptor maturation in immune cells and meiosis in gametes (Khan and Ali, 2017). Moreover, certain developmental processes, such as those found in differentiating neurons, proceed through chromatin-directed DNA damage as an intermediate step (Wu et al., 2021; Wang et al., 2022). Unsurprisingly, mutations in chromatin regulators of DDR, whether inherited or somatically acquired, have been linked to a growing number of human ailments including aging. Thus, aside from providing vital clues about the basic biology of DNA repair, further elucidation of the chromatin response to DNA damage has important implications for human health and disease.
The past decade has witnessed an explosion of explorations in DNA repair in the context of chromatin, driven in part by rapid technological advances. Methods such as ChIP-seq, automated fluorescence imaging, CRISPR screens and proteomics are now routinely employed by researchers to probe DNA-chromatin interactions, and new approaches are continuously being developed. As guest editors of this Research Topic collection, we hope that the articles presented herein will be a valuable resource for the community and help inspire future experimental innovations.
Author contributions
DZ wrote the first draft, BJ and LL reviewed and edited the manuscript. All authors read and approved the final manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Khan, F. A., and Ali, S. O. (2017). Physiological roles of DNA double-strand breaks. J. Nucleic Acids 2017, 6439169. doi:10.1155/2017/6439169
Wang, D., Wu, W., Callen, E., Pavani, R., Zolnerowich, N., Kodali, S., et al. (2022). Active DNA demethylation promotes cell fate specification and the DNA damage response. Science 378 (6623), 983–989. doi:10.1126/science.add9838
Wu, W., Hill, S. E., Nathan, W. J., Paiano, J., Callen, E., Wang, D., et al. (2021). Neuronal enhancers are hotspots for DNA single-strand break repair. Nature 593 (7859), 440–444. doi:10.1038/s41586-021-03468-5
Keywords: DNA damage, DNA repair, chromatin, double strand break, post-translational modifications, pathway choice, clustered damage
Citation: Zong D, Jakob B and Lundholm L (2023) Editorial: DNA damage response in the context of chromatin. Front. Cell Dev. Biol. 10:1095652. doi: 10.3389/fcell.2022.1095652
Received: 11 November 2022; Accepted: 27 December 2022;
Published: 10 January 2023.
Edited and reviewed by:
Sophie A Lelièvre, Institut de Cancérologie de l'Ouest (ICO), FranceCopyright © 2023 Zong, Jakob and Lundholm. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lovisa Lundholm, bG92aXNhLmx1bmRob2xtQHN1LnNl