Understanding dna replication and replication stress as avenues to combat cancer

The Collection “DNA Replication and Replication Stress” brings together original research articles, critical reviews, and perspectives from scientists with diverse viewpoints and areas of

expertise in DNA replication, genome integrity, and cancer. Covering both fundamental and applied science, this collection offers readers insights into the core mechanisms by which cells

replicate their genetic material and maintain the epigenetic marks that regulate its function under normal conditions or when the DNA replication process is perturbed. Fajri and Petryk’s

review1 highlights how recent high-throughput approaches have deepened our understanding of the complexity and plasticity of the eukaryotic chromosomal replication process. Along the same

lines, work by Grasso and collaborators2 demonstrates how direct sequencing of nucleic acids using Nanopore technology provides a powerful means to map ribonucleotides embedded in the genome

with unprecedented resolution, alongside detecting modified bases. In their perspective article, Yadav and Polasek-Sedlackova3 focus on the key roles of minichromosome maintenance proteins

in the spatial and temporal regulation of the DNA replication process. These proteins are critical for licensing replication origins and controlling fork speed, while also performing

non-canonical functions related to chromatin structure and gene expression. Ruggiano and Ramadan4 provide an overview of the mechanisms dedicated to removing replication obstacles, such as

proteins covalently or tightly bound to DNA. Their work discusses how molecular defects in the proteases involved in these mechanisms can result in contrasting outcomes, such as aging and

cancer, even within the same individual. Brosh and collaborators5 offer further insights into the role of replication stress in human diseases, emphasizing it as a key trigger for cellular

senescence, accelerated aging, and inflammation, all of which compromise cellular and organismal function. They also highlight how this knowledge could aid in the design of novel

senotherapeutic approaches. The research articles in the Collection further showcase how disruptions to DNA replication impact the faithful propagation of genetic and epigenetic information,

alter developmental programs, and fuel genome instability, driving tumor initiation and progression when cells bypass genome surveillance mechanisms. A variety of experimental models have

been used to dissect the specific functions of factors involved in the proper execution of the DNA replication process and the DNA damage response (DDR) at replication forks. For example,

the work by Biroccio, Salvati, and colleagues6 highlights a previously unrecognized role of poly (ADP-ribose) polymerase 1 (PARP1) in telomere replication through its interaction with TRF1

during the S-phase. PARP1 was shown to PARylate TRF1, modulating the recruitment of BLM and WRN helicases, thus facilitating telomere replication and preventing telomere fragility. Haccard

et al.7 combined mathematical modeling and experimental approaches in Xenopus laevis to decipher the role of Rif1 in restraining origin firing and ensuring smooth replication timing. The

Boehm laboratory8 provided intriguing insights into the maintenance of genome methylation levels by analyzing zebrafish mutants, showing antagonistic roles for the DNA maintenance methylase

Dnmt1 and the leading strand DNA polymerase epsilon. Alvi and collaborators9 identified Slfn8 and Slfn9 as the mouse functional homologs of human SLFN11, a key factor in the replication

stress response and a determinant of tumor response to chemotherapy. On the other hand, the work of Palovcak and collaborators10 revealed separate roles of the Fanconi anemia-associated

protein FAAP20 in distinct pathways for homology-directed repair of DNA double-strand breaks. Cancer cells frequently rely on backup mechanisms and alternative, often mutagenic, pathways to

repair DNA damage. These adaptations enable cancer cells to survive and proliferate in hostile environments, allowing them to thrive under replication stress. However, these adaptations also

create vulnerabilities. By identifying the mechanisms that cancer cells use to cope with specific DNA lesions and sources of replication stress, researchers have uncovered potential weak

points that could be exploited therapeutically. For instance, Said and collaborators11 identified endogenous R-loops and transcription-associated replication stress as cancer vulnerabilities

that may be targeted for treatment. Wang and collaborators12 discovered a cluster of DDR genes over-expressed in hepatocellular carcinoma (HCC) that are critical for responding to oxidative

lesions. They identified AP2-alpha as a key transcription factor modulating the expression of these genes and showed that a small-molecule inhibitor of AP2-alpha increased oxidative lesions

and sensitized HCC cells to DNA-damaging agents. Ueno and collaborators13 demonstrated that depleting the nucleotide pool using a selective ribonucleotide reductase inhibitor induces

excessive replication stress, impairing cancer cell proliferation, and showed anti-tumor activity of the inhibitor in leukemia and solid tumor models. The Rao group14 showed the potential of

a small molecule, carbazole blue, to inhibit the expression of pro-tumorigenic genes driving unchecked proliferation and aberrant DNA repair, and selectively block breast cancer growth and

metastasis. The work of Yeo and colleagues15 instead provided novel insights into the mechanism of action of an FDA-approved inhibitor targeting the AXL receptor tyrosine kinase. They showed

that AXL inhibition in ovarian cancer induces replication stress and DNA damage, and leads to the upregulation of genes in the cholesterol biosynthesis pathway as a protecting mechanism

limiting DNA damage, opening to potential therapeutic strategies combining AXL inhibition with treatments targeting the DDR or cholesterol biosynthesis. In conclusion, this Collection

presents a mosaic of pieces that, while initially scattered, gradually form a coherent picture, revealing the common thread that connects them. By understanding the normal regulatory

mechanisms of DNA replication and how these processes are altered in cancer cells, researchers can identify critical vulnerabilities—pathways and components necessary for stress adaptation

and unchecked proliferation. Targeting these vulnerabilities could enable the selective eradication of cancer cells without harming normal cells that adhere to established rules and

regulatory controls. The editors at Communications Biology are proud to showcase this selection of work in the exciting area at the intersection of molecular biology and cancer. Although our

Call for papers is formally closed, we remain very interested in publishing papers on the normal mechanisms of DNA replication, how these are perturbed in disease and work that explores how

cancer cells can be specifically targeted through their stress adaptation and alterations of regulatory mechanisms. We would also like to highlight that we, together with Nature

Communications, are currently open for submissions to our Collection on Mitosis and Mitotic defects [https://www.nature.com/collections/bbdfdaaafa]. REFERENCES * Fajri, N. & Petryk, N.

Monitoring and quantifying replication fork dynamics with high-throughput methods. _Commun. Biol._ 7, 729 (2024). Article  PubMed  PubMed Central  Google Scholar  * Grasso, L. et al.

Detection of ribonucleotides embedded in DNA by Nanopore sequencing. _Commun. Biol._ 7, 491 (2024). Article  CAS  PubMed  PubMed Central  Google Scholar  * Yadav, A. K. &

Polasek-Sedlackova, H. Quantity and quality of minichromosome maintenance protein complexes couple replication licensing to genome integrity. _Commun. Biol._ 7, 167 (2024). Article  PubMed 

PubMed Central  Google Scholar  * Ruggiano, A. & Ramadan, K. DNA–protein crosslink proteases in genome stability. _Commun. Biol._ 4, 11 (2021). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Herr, L. M. et al. Replication stress as a driver of cellular senescence and aging. _Commun. Biol._ 7, 616 (2024). Article  PubMed  PubMed Central  Google Scholar  *

Maresca, C. et al. PARP1 allows proper telomere replication through TRF1 poly (ADP-ribosyl)ation and helicase recruitment. _Commun. Biol._ 6, 234 (2023). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Haccard, O. et al. Rif1 restrains the rate of replication origin firing in _Xenopus laevis_. _Commun. Biol._ 6, 788 (2023). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Lawir, D. F. et al. Antagonistic interactions safeguard mitotic propagation of genetic and epigenetic information in zebrafish. _Commun. Biol._ 7, 31 (2024). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Alvi, E. et al. Mouse _Slfn8_ and _Slfn9_ genes complement human cells lacking _SLFN11_ during the replication stress response. _Commun. Biol._ 6, 1038

(2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Palovcak, A. et al. Fanconi anemia associated protein 20 (FAAP20) plays an essential role in homology-directed repair of DNA

double-strand breaks. _Commun. Biol._ 6, 873 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Said, M. et al. FANCD2 promotes mitotic rescue from transcription-mediated

replication stress in SETX-deficient cancer cells. _Commun. Biol._ 5, 1395 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang, C. et al. Macroscopic inhibition of DNA

damage repair pathways by targeting AP-2α with LEI110 eradicates hepatocellular carcinoma. _Commun. Biol._ 7, 342 (2024). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ueno, H. et

al. TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress. _Commun. Biol._ 5, 571 (2022). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Rajamanickam, S. et al. Targeting aberrant replication and DNA repair events for treating breast cancers. _Commun. Biol._ 5, 493 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Yeo, X. H. et al. The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer. _Commun. Biol._

6, 660 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * CNRS UMR9019 Genome Integrity and Cancers, Université

Paris-Saclay, Gustave Roussy, Villejuif, France Valeria Naim Authors * Valeria Naim View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR

Correspondence to Valeria Naim. ETHICS DECLARATIONS COMPETING INTEREST The author is a member of the Communications Biology editorial board. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative

Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as

you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have

permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s

Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not

permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

http://creativecommons.org/licenses/by-nc-nd/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Naim, V. Understanding DNA replication and replication stress as avenues to

combat cancer. _Commun Biol_ 7, 1578 (2024). https://doi.org/10.1038/s42003-024-07250-x Download citation * Published: 27 November 2024 * DOI: https://doi.org/10.1038/s42003-024-07250-x

SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative