Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway.
Brca1 deficiency leads to the development of breast cancer. We previously found that Brca1 deficiency activates the Akt oncogenic pathway. Reduced expression of Brca1 was highly correlated with increased activated Akt in human breast cancer samples. Furthermore, activation of Akt1 was involved in Brca1-deficiency-mediated tumorigenesis in mice. Defective homologous recombination (HR) is thought to be a major contributor to tumorigenesis in Brca1 deficiency. Here, we show that Akt1 promotes chromosome instability in Brca1-deficent cells. DNA breaks in Brca1-deficent cells are aberrantly joined into complex chromosome rearrangements by a process dependent on Akt1. Depletion of Akt1 increases HR in Brca1-mutant cells, which is rescued by expression of wild-type, but not mutant Akt1 with deletion of Brca1-binding domain. Mechanistically, activated Akt1 in Brca1-deficient cells impairs Chk1 nuclear localization and subsequently disrupts interaction of Chk1 and Rad51 leading to HR defects. Our results indicate that Brca1 deficiency might activate Akt1 contributing to tumorigenesis through regulation of the Chk1-Rad51 signaling.
Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, USA.
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Jia
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Song
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D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D000071877:Checkpoint Kinase 1; D043171:Chromosomal Instability / Q000235:genetics; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics; D005260:Female; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D019313:BRCA1 Protein; D011494:Protein Kinases; C514862:Akt1 protein, mouse; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse