BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability.
Numerous human genome instability syndromes, including cancer, are closely associated with events arising from malfunction of the essential recombinase Rad51. However, little is known about how Rad51 is dynamically regulated in human cells. Here, we show that the breast cancer susceptibility protein BRCA2, a key Rad51 binding partner, coordinates the activity of the central cell-cycle drivers CDKs and Plk1 to promote Rad51-mediated genome stability control. The soluble nuclear fraction of BRCA2 binds Plk1 directly in a cell-cycle- and CDK-dependent manner and acts as a molecular platform to facilitate Plk1-mediated Rad51 phosphorylation. This phosphorylation is important for enhancing the association of Rad51 with stressed replication forks, which in turn protects the genomic integrity of proliferating human cells. This study reveals an elaborate but highly organized molecular interplay between Rad51 regulators and has significant implications for understanding tumorigenesis and therapeutic resistance in patients with BRCA2 deficiency.
The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Keiko
K
Yata
The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Jean-Yves
JY
Bleuyard
Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 113-0032, Japan; CREST, Japan Science and Technology Agency (JST), K's Gobancho, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
Ryuichiro
R
Nakato
The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Christine
C
Ralf
Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 113-0032, Japan.
Yuki
Y
Katou
The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Rebekka A
RA
Schwab
The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Wojciech
W
Niedzwiedz
Research Center for Epigenetic Disease, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 113-0032, Japan; CREST, Japan Science and Technology Agency (JST), K's Gobancho, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan.
Katsuhiko
K
Shirahige
The Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: fumiko.esashi@path.ox.ac.uk.
Fumiko
F
Esashi
D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004261:DNA Replication; D005092:Exonucleases / Q000378:metabolism; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D005092:Exonucleases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C551750:BRCA2 protein, human; C495894:CDK2 protein, human; C113574:Rad1 protein, human