Conquering cancer is one of the most crucial missions for researchers of environmental mutagenesis and carcinogenesis. One effective approach to understanding carcinogenesis involves elucidating how mutations are fixed from DNA lesions induced by environmental mutagens and carcinogens and how DNA polymerases and intracellular functions related to these polymerases are involved in the mutation fixation. These are rather old-fashioned but still critical questions that should be clarified. Recent analyses using novel molecular biology and genome epidemiology techniques could be powerful weapons to make open this “black box.” Seven scientists who were working to elucidate the molecular mechanisms for environmental mutagenesis and carcinogenesis were invited to the Public Symposium of the Japanese Environmental Mutagen Society (JEMS) held on May 28, 2011; they discussed the aims of mutation research in the next generation to conquer cancer.
Although there are some similarities and dissimilarities between DNA and RNA polymerase as enzymes, when polymerase encounters a DNA lesion, the polymerase proceeds with one of two actions. One is to stall at the DNA lesion, which results in DNA repair mechanisms or cell death being induced. The other is for the polymerase to bypass the DNA lesion, which results in a mutation that could subsequently lead to carcinogenesis. The effects of DNA lesions, on either DNA polymerases or RNA polymerases, might be dependent on the cell cycle. This is because DNA polymerase in replication and RNA polymerase in transcription operate in the S phase and the G0 phase of the cell cycle in human cells, respectively. In addition, lesions may vary in their effects among the many cell types in the human body. Most differentiated cells, like cardiomyocytes and neurons, are post-mitotic, non-dividing cells. Some somatic cells, stem cells, and cancer cells are dividing cells in which DNA replication occurs in the S phase. To re-evaluate the biological risk conveyed by DNA lesions in living human cells, studies on cell-cycle-dependent actions of both DNA polymerase and RNA polymerase on DNA templates that contain lesions might be required.
Defects in DNA polymerase (Pol) η result in a cancer-prone and UV-sensitive inherited syndrome, a variant form of xeroderma pigmentosum, suggesting that Polη plays a vital role in preventing UV-induced skin cancers. In fact, Polη can catalyze translesion synthesis (TLS) past prominent UV-induced lesions efficiently and accurately. However, Polη is intrinsically an error-prone DNA polymerase, like other TLS polymerases. Biochemical, structural and physiological studies revealed that Polη and other TLS polymerases participate in multiple mutagenic mechanisms, including somatic hypermutation of immunoglobulin genes. Protein-protein interactions between Polη and PCNA, TLS polymerases, RAD18 and DNA repair proteins, as well as their posttranslational modifications, have been shown to be important for regulating Polη.
The mono-ubiquitination of proliferating cell nuclear antigen (PCNA) by the RAD6-RAD18 complex is involved in the regulation of translesion DNA synthesis, which is one of the sub-pathways of post-replication repair. Translesion DNA polymerases that belong to the Y-family of DNA polymerases have ubiquitin interacting domains, which are required for high affinity binding to mono-ubiquitinated PCNA. This suggests an attractive model for mediating polymerase switching in which PCNA is mono-ubiquitinated at the stalled 3′ end of the replication fork, and the mono-ubiquitinated PCNA recruits translesion DNA polymerases for bypass replication. However, the fate of the replicative DNA polymerases at the damage site, the regulatory mechanism(s) governing the ubiquitination and the mechanism(s) controlling the switch back to replicative DNA polymerase after translesion DNA synthesis, are still obscure. Biochemical analyses in general, and reconstitution systems with purified proteins, in particular, provide powerful tools for addressing such questions, and have provided insights into the unexpected nature of polymerase switching. The possibility of whether the biochemical events demonstrated in vitro mimic in vivo cellular events in response to DNA damage is discussed.
Duplication of the genome must be faithfully carried out in proliferating cells. DNA replication is the stage in which DNA damage becomes truly dangerous and potentially causes cell death or genomic instability. DNA damage bypass mechanisms have evolved as the ‘last minute’ processes to protect the quality of genome replication from these risks. Damage bypass provides a highly flexible mechanism to tolerate various types of DNA damage during replication. Recent studies have highlighted that bypass mechanisms can be uncoupled from global genome replication: i.e., the time of action of DNA damage bypass is not fixed at a particular point during genome replication. Although DNA damage bypass mechanisms are conserved throughout organisms, their regulation is different between prokaryotes and eukaryotes. On one hand, the bypass mechanisms of prokaryotes are mainly dependent on upregulation of transcripts under the SOS regulon. On the other hand, in eukaryotes, DNA damage bypass is activated by ubiquitylation of the replication sliding clamp, PCNA. This review starts with our understanding of the basis of lesion-bypassing mechanisms in the bacterial system, advances to recent views of the molecular mechanisms underlying eukaryotic DNA damage bypass and specifically focuses on how the bypassing mechanisms provide temporally and structurally flexible functions.
Translesion DNA synthesis (TLS) is an essential mechanism for DNA damage tolerance during genome duplication by bypassing DNA lesions with use of specialized low-fidelity polymerases. Thus, TLS is inherently mutagenic, which is presumed to be involved in cancer initiation and progression. Increasing attention has focused on post-translational regulatory mechanisms of TLS polymerases, including covalent modification (e.g., phosphorylation) and proteasomal degradation. In this review article, we focus on our findings on Hsp90-mediated regulation of TLS polymerases and discuss potential pharmacological effects of Hsp90 inhibitors in cancer therapy.
Recent advances in genome analysis technologies have provided a detailed genome-wide view of cancerous and non-cancerous cells. Lung cancer is largely caused by tobacco smoking, but several studies have implicated inherited genetic factors in disease etiology. Genome-wide association studies (GWASs) using DNA chips have identified loci/genes with polymorphisms that underlie inter-individual differences in cancer susceptibility, including single nucleotide polymorphisms (SNPs). CHRNA (cholinergic receptor, nicotinic, alpha), TERT (telomerase reverse transcriptase) and TP63 (tumor protein p63) loci have been linked to lung cancer susceptibility by GWASs. SNPs in TERT and TP63 are preferentially associated with the risk of adenocarcinoma, the commonest histological type of lung cancer affecting both smokers and non-smokers, whereas those in CHRNA are associated with lung cancer risk irrespective of histological type. An association of functional polymorphisms in DNA repair/metabolic genes with the risk of squamous cell carcinoma, a major histological type developed in smokers, has been suggested, but it remains inconclusive. It was also suggested that an SNP in the TP53 tumor suppressor gene influences the response to platinum-doublet chemotherapy in lung cancer patients. However, analyses have shown that only a subset of SNPs is involved in lung carcinogenesis/therapy. Further GWASs are needed to translate the information on genetic variations into cancer prevention and clinical practice by focusing on specific subtypes of lung cancers or therapeutic responses.
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