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].