Human TopBP1 participates in cyclin E/CDK2 activation and preinitiation complex assembly during G1/S transition.
Human TopBP1 with eight BRCA1 C terminus domains has been mainly reported to be involved in DNA damage response pathways. Here we show that TopBP1 is also required for G(1) to S progression in a normal cell cycle. TopBP1 deficiency inhibited cells from entering S phase by up-regulating p21 and p27, resulting in down-regulation of cyclin E/CDK2. Although co-depletion of p21 and p27 with TopBP1 restored the cyclin E/CDK2 kinase activity, however, cells remained arrested at the G(1)/S boundary, showing defective chromatin-loading of replication components. Based on these results, we suggest a dual role of TopBP1 necessary for the G(1)/S transition: one for activating cyclin E/CDK2 kinase and the other for loading replication components onto chromatin to initiate DNA synthesis.
Jeon
Yesu
Y
Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.
Lee
Kyung Yong
KY
Ko
Min Ji
MJ
Lee
Yong Sun
YS
Kang
Sukhyun
S
Hwang
Deog Su
DS
D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D054462:p21-Activated Kinases
D002352:Carrier Proteins; D002843:Chromatin; D019927:Cyclin E; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2