Abstract
Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by hypersensitivity to ionizing radiation, chromosomal instability, and a high risk of cancer. A responsible protein NBS1 has been shown to interact with gamma-H2AX, and is essential for homologous recombination repair. However, the mechanism of DNA dsb repair has not yet been fully defined. Recently, mediator proteins such as TopBP1, MDC1 and 53BP1 draw attention to understanding in DNA repair pathway.
TopBP1 shares sequence homology with fission yeast Cut5/Rad4, suggesting its role in damaged DNA repair. It was reported that TopBP1 form nuclear foci with gamma-H2AX, NBS1, PCNA and BRCA1 after DNA damage. In this study, we show that TopBP1 interacts with NBS1. We also found that NBS cells which express NBS1 mutant with defective FHA/BRCT domain showed abnormal formation of TopBP1 foci after DNA damage. TopBP1 knockdown cells showed a decrease of homologous recombination, and an increased frequency of premature chromatin condensation (PCC), which is characteristic for ATR-defective Seckel syndrome cells. It has recently been reported that TopBP1 directly activates ATR. These results suggested that TopBP1 is recruited to damaged DNA sites in an NBS1-dependent manner, and is involved in homologous recombination repair.
