Tomohiko Sugiyama Laboratory
Department of Biological Sciences
- Molecular mechanism of recombinational repair
Significance of DNA Repair Study: from Cancer to Down syndrome
DNA should be accurately copied, divided at every cell division, and transmitted from parents to children without damage, information loss, or duplication. Our DNA is damaged much more frequently than most people imagine. Mammals such as humans experience more than 20,000 DNA damages per day per cell even in the absence of external DNA damaging agents. Therefore, our DNA requires constant repair. Since DNA damage is also induced by environmental factors, including radiation and some chemicals, DNA repair is even more important to our survival. Among all the different types of DNA damage, the DNA double-strand break (DSB) is the most dangerous because the cell cannot survive even one break in the absence of repair. DSB repair must maintain sequence information, because failure to maintain sequence information may be catastrophic for the cell.
If DSB repair is inaccurate, cells may survive but are likely to behave abnormally and in the worst case become cancerous.
Fig. 1. DNA repair and cancer. In many breast cancer cells, DNA double-strand breaks are inaccurately repaired. This results in gross genome rearrangement which results in cancer.
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Fig. 1 shows chromosomes of a breast cancer cell illustrating this point. Note that the cell is aneuploid, e.g., chromosomes 9 and 12 are present in three copies and the colors indicate that many chromosomes are the products of breakage and ligation from two different chromosomes. Consistent with this observation, the breast and ovarian cancer susceptibility genes BRCA1, BRCA2 and other tumor suppressor genes are involved in accurate DNA double-strand break repair. The lack of these gene functions results in inaccurate DNA repair, producing gross chromosome rearrangements that contribute to the development of cancer. Therefore, understanding the mechanisms of DNA double-strand break repair will contribute greatly to our understanding of cancer.
Fig. 2. DNA repair and Down syndrome.
At an early phase of meiosis, DNA double-strand breaks (DSB) are intentionally introduced on chromosomes. Repair of these breaks by DNA recombination connects homologous chromosomes (red and blue). Problems in the repair can cause miscarriages or chromosome disorders (chromosome loss or duplication) like Down syndrome.
DSB repair also plays a crucial role in sexual reproduction. When we produce gametes (egg or sperm) through meiosis, DSB repair leads the recombination of homologous chromosomes (Fig. 2).
Accurate repair of these DSBs by homologous recombination ensures that genetic information is neither lost nor gained in sister chromatids. In addition, the recombination ensures pairing of homologous chromosomes (Fig. 2, "Homologous Pairing") that is essential for correct distribution of chromosomes into gametes. Without accurate homologous pairing, chromosomes are distributed randomly into gametes resulting in aneuploidy. Most aneuploidies in embryos are lethal and result in early miscarriages. However, some aneuploid gametes can contribute to live births of individuals that have an incorrect number of chromosomes resulting in genetic diseases such as Down syndrome and Klinefelter syndrome. Therefore, understanding the mechanisms of DNA double-strand break repair will also contribute greatly to our understanding of diseases that arise due to chromosome disorders.