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Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses

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Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations. These genetic syndromes typically displaying mutations in DNA repair/DDR-related genes are often called “genome instability syndromes.” Common features of these hereditary syndromes include a high incidence of cancers and developmental abnormalities including short stature, microcephaly, and/or neurological deficiencies. However, precisely how impaired DNA repair and/or dysfunctional DDR pathologically promote(s) these syndromes are poorly understood. In this review article, we summarize the clinical symptoms of several representatives “genome instability syndromes” and propose the plausible pathogenesis thereof.

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Abbreviations

DSB:

Double-strand DNA break

DDR:

DNA damage response

NER:

Nucleotide excision repair

TLS:

Translesion DNA synthesis

CNS:

Central nervous system

ICL:

Interstrand crosslink

HR:

Homologous recombination

NHEJ:

Non-homologous end-joining

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Acknowledgements

We thank Dr. Margaret Biswas, from Edanz group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This study is partially funded by the Practical Research Project for Rare/ Intractable Diseases, Japan Agency for Medical Research and Development, AMED to KH; a Grant-in-Aid for Scientific Research (C) (grant number 16K07119), Japan Society for the Promotion of Science (JSPS), The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan to TT.

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  1. Department of Pharmacology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan

    Takeshi Terabayashi

  2. Clinical Engineering Research Center, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan

    Katsuhiro Hanada

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Terabayashi, T., Hanada, K. Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses. Cell Biol Toxicol 34, 337–350 (2018). https://doi.org/10.1007/s10565-018-9429-x

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