C99
Role of LATS1 in DNA damage signalling
Robert Latusek, Cecilia Lundin, Thomas Helleday, Eric O'Neill
University of Oxford, UK
Background
RASSF1A is a tumour suppressor epigenetically silenced in sporadic human malignancies. Re expression of RASSF1A promotes cell cycle arrest and apoptosis. A key signalling pathway through which RASSF1A exerts it effect requires the kinases MST2 / LATS1 and subsequent stabilisation of a YAP1/p73 transcriptional complex. We have recently described a role for RASSF1A in the DNA damage dependent stabilisation of p73, which also requires MST2 and LATS1 [1].
LATS kinases are also documented regulators of cyclin dependent kinases (CDKs) [2]. We wanted to investigate if LATS-CDK binding can be stimulated by RASSF1A which may contribute to its tumour suppressor effects.
Results
The results described here are aimed to elucidate the how DNA damage induced LATS activation may regulate CDK dependent events. LATS1 has been described to been required for homologous recombination (HR) after DNA damage in M-phase [3], a process whereby a key mediator of HR, BRCA2, is regulated by CDKs [4]. We have identified that activation of LATS1 in response to DNA damage promotes association with CDK1 and CDK2 which in turn prevents association with BRCA2. Therefore LATS1 may play a role in HR by restricting CDK function.
References
[1] Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Piazzolla D, Baccarini M, Vass JK, Kolch W, and ONeill E (2007), RASSF1A Elicits Apoptosis through an MST2 Pathway Directing Proapoptotic Transcription by the p73 Tumour Suppressor Protein, Molecular Cell 27, 962975
[2] Turenchalk GS, St. John MAR, Tao W, Xu T (1999), The role of lats in cell cycle regulation and tumourigenesis, Biochemica et Biophysica Acya 1424, M9-M16
[3] Matsuoka S, Ballif BA, Smogorzewska A, McDonald III R, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Shiloh Y, Gygi SP, Elledge SJ (2007), ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage, Science 316,1160-1166
[4] Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M and West S (2005), CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair, Nature 434, 598-604
