Review ArticleA concise review of DNA damage checkpoints and repair in mammalian cells
Introduction
The genome of eukaryotic cells is under constant attack. A wide diversity of lesions caused by environmental agents such as ultraviolet (UV) radiation in sunlight, ionizing radiation, and numerous genotoxic chemicals can arise in the DNA. In addition, the genome is also threatened from within. By-products of normal cellular metabolism, such as reactive oxygen species (ROS; i.e., superoxide anions, hydroxyl radicals, and hydrogen peroxide) derived from oxidative respiration and products of lipid peroxidation, can cause a variety of damages in the DNA (Fig. 1).
On the other hand, DNA-damaging agents such as ionizing radiation, UV light (photodynamic therapy), and most chemotherapeutic agents are increasingly being used to treat common disorders like arterial (re)stenosis (brachytherapy and drug-eluting stents) or cancer.
Whereas DNA damage in terminally differentiated cells (such as muscle cells) gives rise to DNA damage repair to ensure the integrity of the transcribed genome, the induction of DNA damage in dividing cells results in the activation of cell cycle checkpoints. These checkpoints halt the proliferating cell in its cell cycle progression in order to give time to the DNA damage repair machinery to do its work, thereby avoiding incorrect genetic information from being passed onto the progeny. Especially when mutations are accumulating, the chance of developing uncontrolled cell growth (oncogenesis) is substantial. A variety of lesions can occur in the DNA, including single- and double-strand breaks (DSBs), mismatches, and chemical adducts. Therefore, multiple repair pathways have evolved, each directed to a specific type of lesion. Each pathway consists of numerous proteins forming a cascade in order to repair the damage as accurate as possible.
Eventually, when the repair process fails, the cell cycle can be blocked permanently, leading to a senescent state of the cell, or alternatively, apoptosis may be induced. Both mechanisms prevent potentially harmful cells from dividing, ensuring that no mutations are inherited by the next generation of cells.
Section snippets
Cell cycle checkpoints
The cell cycle in eukaryotic cells consists of four phases, gap (G)1, synthesis (S), G2, and mitosis (M), and one phase outside the cell cycle, G0 (Fig. 2). In the G1 phase, directly after mitosis, the cell increases in size and starts synthesizing RNA (transcription) and proteins (translation). In the subsequent S phase, DNA is replicated to produce an exact copy of the genome for the subsequent daughter cells. During G2, the cell will grow and make extra proteins to ensure that two viable
DNA damage repair
DNA damage checkpoints can only prevent the transduction of mutations to daughter cells by means of an efficient DNA damage repair machinery. As there are many different lesions possible, different types of repair pathways have evolved. Important pathways in mammalian cells include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and DSB repair (Fig. 5A–D).
Concluding remarks
Over the past 30 years, our knowledge about DNA damage, DNA damage checkpoints, and DNA repair has increased dramatically. This brief review should be regarded as an introduction to the knowledge accumulated over those years. It should be emphasized that many issues remain unsolved yet. However, the concept of DNA damage and repair is very important for our understanding of the pathogenesis and treatment of many disease processes.
Acknowledgments
We would like to thank Dr L.R. van Veelen for kindly providing Fig. 2, Fig. 3, Fig. 5 and A.K. Dik for valuable help with the other figures. Also, we would like to thank V. Smits and J. Essers for carefully reading the manuscript.
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Funded by Netherlands Heart Foundation Grant No. 99118.