When mutations affect tumor suppressor genes or oncogenes, cell might transform into cancer cells. Therefore, DNA repair is essential for preventing tumor development. However, once a cancer has developed, DNA damage can be exploited to reduce cancerous growth and evoke apoptotic demise of cancer cells. Thus, chemo- and radiotherapies are still today, over 60 years after having been first introduced into tumor therapy, important strategies to fight cancer.
Given the central role of genome instability in triggering and treating cancer, it is likely that genotoxic treatments will remain an important avenue of cancer therapy. Also the better understanding of DNA repair systems will allow therapies that specifically target selected repair pathways.
It will be of particular importance to gain a deeper understanding how the various DNA repair systems interact with each other in the context of cellular homeostasis and DNA metabolism in order to optimize targeted approaches to cancer therapy. 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.
Aas, P. Nature , — Adamo, A. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Cell 39, 25— Alexanian, R. Melphalan therapy for plasma cell myeloma. Blood 31, 1— Google Scholar. Allen, C. Heavy charged particle radiobiology: using enhanced biological effectiveness and improved beam focusing to advance cancer therapy. Arora, S. DNA Repair. Bakkenist, C. Bartek, J. Chk1 and Chk2 kinases in checkpoint control and cancer.
Cancer Cell 3, — Baskar, R. Cancer and radiation therapy: current advances and future directions. Begg, A. Strategies to improve radiotherapy with targeted drugs. Bonate, P. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Drug Discov. Bootsma, D. Scriver, A. Beaudet, W. Sly, D. Valle, B. Childs, K. Kinzler, et al. Brooks, P. Brown, E. ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
Genes Dev. Bryant, H. PARP is activated at stalled forks to mediate Mredependent replication restart and recombination. EMBO J. Burger, H. Drug transporters of platinum-based anticancer agents and their clinical significance.
Drug Resist. Caestecker, K. Cell Res. Cerbinskaite, A. Defective homologous recombination in human cancers. Cancer Treat. Chambon, P. Chan, J.
Oral altretamine used as salvage therapy in recurrent ovarian cancer. Ciccia, A. The DNA damage response: making it safe to play with knives.
Cell 40, — Cimprich, K. ATR: an essential regulator of genome integrity. Cell Biol. Clarke, M. The role of membrane transporters in cellular resistance to anticancer nucleoside drugs. Cleaver, J. Defective repair replication of DNA in xeroderma pigmentosum. Cancer in xeroderma pigmentosum and related disorders of DNA repair.
Cancer 5, — Crossan, G. Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. Curtin, N. DNA repair dysregulation from cancer driver to therapeutic target. Cancer 12, — Damia, G. Cisplatinum and taxol induce different patterns of p53 phosphorylation. Neoplasia 3, 10— Dasari, S. Cisplatin in cancer therapy: molecular mechanisms of action. Day, R. Deans, A. DNA interstrand crosslink repair and cancer. Cancer 11, — De Bont, R. Endogenous DNA damage in humans: a review of quantitative data.
Mutagenesis 19, — Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair.
De Weerd-Kastelein, E. Genetic Heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization. New Biol. Delaney, G. The role of radiotherapy in cancer treatment. Cancer , — Diderich, K.
Premature aging and cancer in nucleotide excision repair-disorders. Elvers, I. UV stalled replication forks restart by re-priming in human fibroblasts. Nucleic Acids Res. Emadi, A. Cyclophosphamide and cancer: golden anniversary. Evans, E. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. Ewald, B. Nucleoside analogs: molecular mechanisms signaling cell death. Oncogene 27, — Fagbemi, A. Regulation of endonuclease activity in human nucleotide excision repair.
Ferry, K. Fink, D. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. Fitch, M. The DDB2 nucleotide excision repair gene product p48 enhances global genomic repair in p53 deficient human fibroblasts. Fu, D. Balancing repair and tolerance of DNA damage caused by alkylating agents. Furgason, J. Targeting DNA repair mechanisms in cancer. Galanski, M. Recent developments in the field of anticancer platinum complexes. Anticancer Drug Discov.
Galluzzi, L. Molecular mechanisms of cisplatin resistance. Oncogene 31, — Galmarini, C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol. Genini, D. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 96, — Gnewuch, C. A critical appraisal of the evolution of N -Nitrosoureas as anticancer drugs.
Guillotin, D. Exploiting DNA mismatch repair deficiency as a therapeutic strategy. Hakem, R. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85, — Hall, E. Radiobiology for the Radiologist , 7th Edn. Hanawalt, P. Transcription-coupled DNA repair: two decades of progress and surprises. Science — Cellular metabolic stress: considering how cells respond to nutrient excess.
Mol Cell 40 2 — Anastasiou D. Tumour microenvironment factors shaping the cancer metabolism landscape. Br J Cancer 3 — Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife 6:e Regulation of cancer cell metabolism. Nat Rev Cancer 11 2 — The emerging hallmarks of cancer metabolism.
Cell Metab 23 1 — Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14 2 Fundamentals of cancer metabolism. Sci Adv 2 5 :e The causes and consequences of genetic heterogeneity in cancer evolution. Nature — Genomic landscape of DNA repair genes in cancer.
Oncotarget 7 17 — DNA repair targeted therapy: the past or future of cancer treatment? Pharmacol Ther — Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 16 2 — DNA methylation and the regulation of gene transcription. Cell Mol Life Sci 59 2 — The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem — Roles of chromatin remodellers in DNA double strand break repair. Exp Cell Res 1 — Sinha M, Peterson CL.
Chromatin dynamics during repair of chromosomal DNA double-strand breaks. Epigenomics 1 2 — Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr 8 Suppl S—5S. PubMed Abstract Google Scholar. Acetyl coenzyme A: a central metabolite and second messenger.
Cell Metab 21 6 — The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat Cell Biol 19 11 — The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15 8 — Mol Cell 67 2 — ATP-citrate lyase: a key player in cancer metabolism. Cancer Res 72 15 — Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate.
Cancer Metab Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27 1 — Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature —6. Integrative modelling of tumour DNA methylation quantifies the contribution of metabolism. Nat Commun Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation.
Nat Cell Biol 17 9 — Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature —7. DNA damage and repair modify DNA methylation and chromatin domain of the targeted locus: mechanism of allele methylation polymorphism.
Sci Rep Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci 39 8 — New York, Freeman, Sinha, R. Photochemical and Photobiological Sciences 1 , — Restriction Enzymes. Genetic Mutation. Functions and Utility of Alu Jumping Genes. Transposons: The Jumping Genes. DNA Transcription.
What is a Gene? Colinearity and Transcription Units. Copy Number Variation. Copy Number Variation and Genetic Disease.
Copy Number Variation and Human Disease. Tandem Repeats and Morphological Variation. Chemical Structure of RNA. Eukaryotic Genome Complexity. RNA Functions. Citation: Clancy, S. Nature Education 1 1 DNA integrity is always under attack from environmental agents like skin cancer-causing UV rays.
Aa Aa Aa. Table 2. Figure Detail. Figure 1. Figure 3. Figure 2. Additional DNA Repair mechanisms. Figure 4. References and Recommended Reading Branze, D. Thomas, Lodish, H. New York, Freeman, Sinha, R. Repairing damage in DNA from anything that causes a mutation, such as UV radiation and tobacco smoke, is a fundamental process that protects our cells from becoming cancerous.
In the study published in the journal Nature , the scientists analysed more than 20 million DNA mutations from 1, tumours across 14 cancer types. They found that in many cancer types, especially skin cancers, the number of mutations was particular high in regions of the genome known as 'gene promoters'. Significantly, these DNA sequences control how genes are expressed which in turn determine cell type and function. The researchers showed that the numbers of DNA mutations are increased in gene promoters because the proteins that bind DNA to control gene expression block one of our cell repair systems responsible for fixing damaged DNA.
This system is known as nucleotide excision repair NER and is one of a number of DNA repair mechanisms that occurs in human cells and the only one capable of repairing damage from UV light. Internationally, scientists have so far identified only one promoter mutation, known as the telomerase reverse transcriptase TERT gene, that definitively contributes to cancer.
0コメント