BRCA1 downregulates the kinase activity of Polo-like kinase 1 in response to replication stress.
In response to DNA damage or replication stress, proliferating cells are arrested at different cell cycle stages for DNA repair by downregulating the activity of both the cyclin-dependent kinases (CDKs) and other important cell cycle kinases, including Polo-like kinase 1 (PLK1) . The signaling pathway to inhibit CDKs is relatively well understood, and breast cancer gene 1 (BRCA1) and other DNA damage response (DDR) factors play a key role in this process. However, the DNA damage-induced inhibition of PLK1 is still largely a mystery. Here we show that DNA damage and replication stress stimulate the association between BRCA1 and PLK1. Most importantly, we demonstrate that BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of Aurora A, hBora, and PLK1. Together with previous findings, we propose that in response to replication stress and DNA damage, BRCA1 plays a critical role in downregulating the kinase activity of both CDKs and PLK1.
Basic Biomedical Science Division, Sanford School of Medicine, The University of South Dakota, Vermillion, SD, USA.
Jianqiu
J
Zou
Khosrow
K
Rezvani
Hongmin
H
Wang
Kyung S
KS
Lee
Dong
D
Zhang
D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics*; D000097869:Polo-Like Kinase 1
D064096:Aurora Kinase A; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C492913:BRCA1 protein, human; C528235:bora protein, human; C576917:AURKA protein, human
BRCA1; DNA damage; PLK1; replication stress