Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses
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.
KeywordsCancers DNA lesions Double-strand DNA breaks Genetic disorders
Double-strand DNA break
DNA damage response
Nucleotide excision repair
Translesion DNA synthesis
Central nervous system
We thank Dr. Margaret Biswas, from Edanz group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Graham JM Jr, Anyane-Yeboa K, Raams A, Appeldoorn E, Kleijer WJ, Garritsen VH, et al. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am J Hum Genet. 2001;69(2):291–300.PubMedCrossRefGoogle Scholar
- Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR, et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am J Hum Genet. 2007;80(3):457–66.PubMedPubMedCentralCrossRefGoogle Scholar
- de la Rojo, Vega M, Krajisnik A, Zhang DD, Wondrak GT. Targeting NRF2 for improved skin barrier function and photoprotection: focus on the achiote-derived apocarotenoid bixin. Nutrients. 2017;9(12)Google Scholar