DNA修復と子どもの(先天的)疾患

The functional integrity of DNA repair is crucial because in principle, most of diseases are related to gene malfunction both/either directly and/or indirectly. Especially, childhood diseases is highly related to multiple important gene mutation including childhood cancer(9), neurodevelopmental diseases(8). DNA repair could significantly affects frequency of incidental gene mutation whose degree is 1000-folds(6). Therefore, germline mutation on DNA repair is high risk predisposition of genetic disease including cancer(4,5), neurodevelopmental diseases(7) and the other rare diseases. In principle, germline mutation affects whole cells in human body, so malfunction of DNA repair affects all regions in body. However, DNA repair mechanism is diverse(10) and many genes over one hundred may affect DNA repair(11), so complemental system may exist even if a part of gene related to DNA repair is mutated. Therefore, we need to understand comprehensive mechanisms about DNA repair and identify board gene associated with respective DNA repair mechanisms. Especially, in childhood, whole body grow rapidly, meaning active cellular differentiation and propagation occur in cellular level. Therefore, functional integrity of broad DNA repair systems also for single nucleotide variant such as mismatch repair, Base Excision Repair (BER), Nucleotide Excision Repair (NER), Direct Repair (DR) is more important than adult. 

Of course, DNA has molecular structure mainly composed of hydrogen, phosphorous, oxygen, carbon(1), so these structure could break (damage) by the external energy (stress), like ionic radiation, UV radiation, arbitrary chemical reaction including function of enzyme. These damage could arise in whole region of gene including both cording region and non-cording region. Therefore, not only gene sequences determining protein molecular structure(cording region), but also determining factor for efficiency of transcription associated with the transition process from gene information to specific protein production (promoter region (non-cording region)) could receive structural damage, resulting malfunction. However, an organism has redundant system of gene including a human. For example, chromatin replicates sister chromatid in S phase of a cell. This sister chromatid is copy of specific chromatin, so in principle, sister chromatid has highly similar molecular structure with original chromatin. When double strand structure receives damage, this damaged chromatin search sister chromatid having similar molecular structure, and DNA strand structure is recovered (repaired) through cross-linking of strand region of original chromatin and sister chromatid(2). Existence of whole sister chromatid able to be accessed in cell nucleus is limited to period of cell phase from the replication of sister chromatid to the mitosis, so this repair system called homologous recombination is limited to S phase and G2 phase(3). 

DNA can undergo a variety of modifications, including strand breaks, base damage, helical
distortions and strand cross-links(7). 

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