Recent progress in research on DNA damage responses in animals and plants

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Maintaining genome integrity is essential for the faithful transmission of genetic information to offspring as well as for individual survival. However, genome integrity is constantly threatened by genotoxins from environmental sources (e.g., ionizing radiation and ultraviolet light) and from normal metabolic processes (e.g., reactive oxygen species production) during the lifespan of an organism. Cells have therefore evolved a collection of sophisticated signaling networks, the DNA damage responses (DDRs), to counter such threats. DDRs are composed of DNA damage recognition, signal transduction, and the activation of cellular responses including DNA repair, cell cycle arrest and programmed cell death, and multiple proteins are involved in DDR signaling networks. Mutations in human DDR-related genes are associated with a wide variety of diseases and cancer predisposition syndromes; accordingly, it is clear that DDRs are crucial for cell survival. ATM (ataxia telangiectasia mutated) is a serine/threonine protein kinase and is a key signal transducer in one of the DDR pathways. ATM is mainly required for the cell's response to double-strand breaks (DSBs), and ATM mutations in humans lead to the inherited disease ataxia telangiectasia (A-T), which shows pleiotropic defects including progressive neurodegeneration, telangiectasia, genomic instability, immunodeficiency and sensitivity to ionizing radiation. ATR (ATM-Rad3-related) is another important serine/threonine protein kinase; it responds to single-stranded DNA damage. Humans that survive with ATR mutations develop Seckel syndrome, which is characterized by growth retardation and microcephaly. The tumor suppressor p53 is a transcription factor that regulates many genes involved in DDRs, and consequently regulates cell cycle arrest, DNA repair or apoptosis. The p53 gene is mutated in more than 50% of human cancers. These observations indicate that DDRs act to maintain genome stability and thus protect the organism against various diseases including cancer.

It is important to understand the mechanism of DDRs for cancer chemotherapy. Genotoxic drugs, which artificially induce DNA damage, have been used in cancer chemotherapy for 30 years. Rapidly dividing cancer cells, which actively synthesize new DNA, are particularly sensitive to genotoxic agents. If excess DNA damage occurs, cancer cells undergo apoptosis. Camptothecin (CPT) and CPT analogs, which inhibit DNA topoisomerase I, are used for cancer chemotherapy. CPT induces DNA strand breaks mediated by DNA replication and RNA transcription, and the resulting DNA damage has a characteristic structure that differs from DSBs. Therefore, the cellular response to CPT-induced DNA damage is different from that to DSBs. In this issue of Genes and Genetic Systems, Ryo Sakasai and Kuniyoshi Iwabuchi introduce their latest data regarding the cellular response to CPT-induced DNA damage.

Furthermore, a number of compounds that target DDR pathways directly have gained recent attention as potential anticancer drugs and are currently under clinical evaluation. Their targets include the protein kinases involved in cell cycle DNA checkpoints that are induced by replication stress and DNA damage. Because DDR defects are associated with cancer development, it may seem counterintuitive to inhibit DDR pathways for cancer chemotherapy. However, DDRs also have a negative effect in contributing to resistance to chemo- and radiotherapy. Therefore, inhibitors of DDR pathways can act as anticancer drugs.

In the past few years, the relationship between DDRs and chromatin has been examined. Because genomic DNA in eukaryotic cells is packaged with histones to form the chromatin structure, the generation of DNA lesions and the resulting activation of DDRs are both affected by the chromatin status at the site of damaged DNA. Chromatin structure is subject to at least three regulatory mechanisms: histone modifications, replacement of histones with histone variants, and chromatin remodeling. In this issue, Yuichiro Saito, Hui Zhou and Junya Kobayashi review the function of NBS1, a multifunctional protein that is involved in various DDR processes, and its relationship with histone modification and chromatin remodeling.

Compared to animal DDRs, studies of plant DDRs are at an earlier stage. However, plants are of interest for these studies owing to their distinct lifestyle. Whereas animals move freely, plants are sessile and usually grow in the ground, preventing their escape from environmental stress. Furthermore, plants have the unique ability to grow continuously and to develop new organs post-embryonically. After the completion of genome sequencing for Arabidopsis thaliana, it became apparent that plant DDRs are similar to those of animals because several human DDR orthologs were identified. However, some important DDR factors, such as the genes encoding DNA-PK (DNA-dependent protein kinase), p53 and CHK1/CHK2 (checkpoint kinases), are missing from the A. thaliana genome. Instead, several plant-specific DDR factors have been found. These observations indicate that plant DDRs have both similarities to and differences from animal DDRs. Thus, I summarize our current knowledge of plant DDRs and the function of the master regulator SOG1, which is a plant-specific DDR transcription factor. Comparisons among the DDR mechanisms of animals and plants are important to understand how DDR systems have evolved. Such studies may also provide insights into DDR strategies that are adapted to particular lifestyles. Clearly, much future research is necessary to clarify these points.