Genome maintenance mechanisms for preventing cancer
Jan H. J. Hoeijmakers
MGC Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus University, PO Box 1738, 3000DR Rotterdam, The Netherlands (e-mail: Hoeijmakers@gen.fgg.eur.nl)
The early notion that cancer is caused by mutations in genes critical for the control of cell growth impliedthat genome stability is important for preventing oncogenesis. During the past decade, knowledge about the mechanisms by which genes erode and the molecular machinery designed to counteract this time-dependent genetic degeneration has increased markedly. At the same time, it has become apparent that inherited or acquired deficiencies in genome maintenance systems contribute significantly to the onsetof cancer. This review summarizes the main DNA caretaking systems and their impact on genome stability and carcinogenesis.
ancer is a disease of our genes. Over time, DNA accumulates changes that activate protooncogenes and inactivate tumour-suppressor genes. The genetic instability driving tumorigenesis is fuelled by DNA damage and by errors made by the DNA machinery. However,‘spontaneous’ mutations are insufficient to explain the lifetime cancer risk1. Indeed, numerous links have been identified between oncogenesis and acquired or inherited faulty genome guardians that cause a ‘mutator’ phenotype, highlighting the key role of DNA protection systems in tumour prevention. Here I focus on the main DNA maintenance mechanisms operating in mammals — nucleotide- and base-excisionrepair, homologous recombination, end joining, mismatch repair and telomere metabolism — and their relevance for cancer.
miscoding uracil, hypoxanthine, xanthine and thymine, respectively4. Figure 1a summarizes some of the most common types of DNA damage and their sources.
The consequences of DNA injury
The outcome of DNA damage is diverse and generally adverse (Fig. 1b). Acute effects arise fromdisturbed DNA metabolism, triggering cell-cycle arrest or cell death. Longterm effects result from irreversible mutations contributing to oncogenesis. Many lesions block transcription, which in effect inactivates every gene containing damage on the transcribed strand — an outcome directly related to gene length. This has elicited the development of a dedicated repair system, transcription-coupledrepair (TCR), which displaces or removes the stalled RNA polymerase and assures highpriority repair. Transcriptional stress, arising from persistent blockage of RNA synthesis, constitutes an efficient trigger for p53-dependent apoptosis (see ref. 5 and the article in this issue by Evan and Vousden, pages 342–348), which may be a significant anti-cancer mechanism. Lesions also interfere with DNAreplication. Recently, a growing class of DNA polymerases, numbered to , was discovered which seems devoted specifically to overcoming damage-induced replicational stress6,7. These special polymerases take over temporarily from the blocked replicative DNA polymerase- / (pol / ), and possibly from pol (Fig. 2, follow upper strand). They have more flexible base-pairing properties permittingtranslesion synthesis, with each polymerase probably designed for a specific category of injury. The number of polymerases preferring damaged templates currently exceeds that for undamaged DNA, which illustrates the magnitude of the problem. But this solution generally comes at the expense of a higher error rate. In fact, this process is responsible for most of damage-induced point mutations8 and is thusparticularly relevant for oncogenesis. Nevertheless, translesion polymerases still protect the genome. For instance, inherited defects in pol- , which specializes in relatively error-free bypassing of UV-induced cyclobutane pyrimidine dimers, cause the variant form of the skin cancerprone disorder xeroderma pigmentosum9,10. In the yeast Saccharomyces cerevisiae, a second, probably even more...