Abstract
Nijmegen syndrome is the genetic disorder, which is characterized by high sensitivity to radiation, chromosome instability and aberrant cell cycle checkpoint. NBS1, the gene responsible for Nijmegen syndrome, forms a protein complex with hMRE11 nuclease and hRAD50, and functions in homologous recombination (HR) repair from DNA double strand breaks, which are elicited by ionizing radiation or other stresses. NBS1 also binds to ATM at the C-terminus and disruption of the interaction fails to recruit ATM to damage sites. Both ATM and NBS1 could have pivotal roles in regulations of cell cycle checkpoints. Therefore, the chromosome instability in NBS cells is considered to be due to defects in both DNA repair and cell cycle checkpoints.
Thus, DNA repair and cell cycle checkpoint genes are responsible for genome instability. However, it is suggested that genome instability in tumor is related to centrosome aberration. Centrosome is the complex organelles comprising two microtuble-based centrioles surrounded by a protein matrix (pericentriolar material, PCM) and other structural elements, a key regulator for chromosome separation in mitosis. Proper centorosome duplication and spindle formation are crucial for prevention of chromosomal instability. Therefore, the normal function of centrosome is essential for maintenance of genome stability. Recent studies suggest that DNA repair factors are involved in centrosome function.
When we examined the localization of NBS1 and ATM by using both protein antibodies, they showed to be accumulated in centrosomes. Moreover, NBS cells showed defect in centrosome amplification, suggesting an indispensable role of NBS1 in centrosome maintenance. We further discuss this novel role of NBS1 in centrosome maintenance.
