Ultraviolet (UV) irradiation causes various types of DNA damage, which leads to specific mutations and the emergence of skin cancer in humans, often decades after initial exposure. Different UV wavelengths cause the formation of prominent UV-induced DNA lesions. Most of these lesions are removed by the nucleotide excision repair pathway, which is defective in rare genetic skin disorders referred to as xeroderma pigmentosum. A major role in inducing sunlight-dependent skin cancer mutations is assigned to the cyclobutane pyrimidine dimers (CPDs). In this review, we discuss the mechanisms of UV damage induction, the genomic distribution of this damage, relevant DNA repair mechanisms, the proposed mechanisms of how UV-induced CPDs bring about DNA replication-dependent mutagenicity in mammalian cells, and the strong signature of UV damage and mutagenesis found in skin cancer genomes.
DNA fulfills two critical roles in a cell by being the template for both DNA replication and RNA transcription. During evolution, eukaryotic cells have adopted multiple strategies to coordinate these two processes to prevent or minimize conflicts that might arise between them. Here, we review the strategies employed by cells to simultaneously accommodate the machineries carrying out DNA replication and transcription, and the mechanisms that are brought into play for resolving conflicts when they do arise. We focus on a group of the so-called ‘difficult-to-replicate’ loci in the human genome, which include chromosome fragile sites, the ribosomal DNA, and telomeres. A failure to resolve conflicts arising between replication and transcription can lead to genome instability, as well as to the initiation of cancer and other age-associated diseases. Understanding the mechanisms required for the resolution of these conflicts could, therefore, open up new therapeutic avenues.
Genome stability and integrity are constantly challenged by exogenous insults such as bacterial infections. When genome stability is perturbed, oncogenic transformation can ensue. Helicobacter pylori (H. pylori) infection is a driving factor of gastric cancer, which is the third leading cause of cancer-related mortality worldwide. Mechanistically, H. pylori infection drives inflammation and directly or indirectly induces DNA damage such as oxidative damage and double-strand breaks (DSBs) in host cells. In addition, the resulting genetic and/or epigenetic perturbations alter the choice of DNA repair pathways. These changes result in imprecise DNA repair, genomic instability as well as chromosomal aberrations that eventually lead to gastric carcinogenesis. In this review, we summarize the mechanisms how H. pylori infection cause DNA damage and alter the DNA damage response pathways in host cells. We highlight the relationship between H. pylori infection and genomic instability that can lead to gastric cancer and propose a potential strategy to interrupt gastric carcinogenesis.
Replicative senescence and crisis are proliferative barriers, activated as a response to telomere shortening and the resulting loss of chromosome end protection. Cells that enter replicative senescence usually maintain a stable genome, while bypass of senescence through loss of p53 and Rb pathways leads to the accumulation of chromosomal end-to-end fusions. Such fusions activate the spindle assembly checkpoint and a cell death program referred to as replicative crisis. Crisis is remarkably effective in removing cells that have bypassed senescence from the population; however, rarely cells escape, which then are thought to progress to a malignant phenotype. These observations suggest that crisis is the final barrier against cancer formation, yet it is still poorly understood how cells die in crisis, in which molecular cascades play a role in escape from crisis, and whether cells that emerge from crisis can be considered as cancer cells, pinpointing that a better understanding of these pathways is critical to target cancer formation in its earliest stages.