ATM-DEPENDENT PHOSPHORYLATION OF BRCA1 AND ITS BIOLOGICAL SIGNIFICANCE

BRCA1蛋白在未经照射的正常人二倍体细胞的细胞核内形成离散的FOCI。作为对电离辐射的响应，BRCA1蛋白重新定位并形成点状FOCI，与Rad50/MRE11/NBS1蛋白形成的FOCI相似，但定位不同。由于在不含BRCA1蛋白的HCC1937中，P53的积累和磷酸化被抑制，这表明BRCA1蛋白在ATM依赖的信号转导中起作用。中心体是指在细胞周期从G1期到S期的过程中复制的有机体。一对中心体起A分裂极的作用，纺锤体纤维由此形成。在HCC1937细胞中，经常检测到中心体异常，提示BRCA1蛋白参与了辐射后中心体的稳定。由于中心体异常会导致染色体的非整倍体，因此BRCA1蛋白的ATM-DEPEPDENT磷酸化可能会抑制中心体的过度复制。

BRCA1 PROTEINS FORM DISCRETE FOCI IN THE NUCLEUS OF UNIRRADIATED NORMAL HUMAN DIPLOID CELLS. IN RESPONSE TO IONIXING RADIATION, BRCA1 PROTEINS RELOCATE AND FORM PUNCTATED FOCI, WHICH ARECLOSELY RELATED TO THOSE FORMED BY RAD50/MREll/NBS1 PROTEINS, BUT IN DIFFERENT LOCALIZATION. BECAUSE P53 ACCUMULATION AND PHOSPHORYLATION WAS SUPPRESSED IN HCC1937, WHICH DOES NOT CONTAIN BRCA1 PROTEIN, IT IS SUGGESTED THAT BRCA1 PROTEINS PLAY A ROLE IN ATM-DEPENDENT SIGNAL TRANSDUCTBRCA1 WAS ALSO FOUND TO COLOCALIZE IN THE CENTROSOMES AFTER X-IRRADIATION. CENTROSOMES ARE THE ORGANELLA, WHICH DUPLICATE DURING CELL CECYLE PROGRESSION THROUGH G1 TO S PHASE. A PAIR OF CENTROSOME FUNCTIONS AS A DIVISION POLAR FROM WHICH SPINDLE FIBERS ARE FORMED. IN HCC1937 CELLS, CENTROSOMAL ABNORMALITY WAS FREQUENTLY DETECTED, SUGGESTING THAT BRCA1 PROTEINS ARE INVOLVED IN CENTROSOMAL STABILITY AFTER IRRADIATION. BECAUSE CENTROSOMAL ABNORMALITY RESULTS IN ANEUPLOIDY OF THE CHROMOSOMES, ATM-DEPEPDENT PHOSPHORYLATION OF BRCA1 PROTEIN MAY SUPPRESS OVER REPLICATION OF THE CENTOROSOMES.