title: RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2.
abstract: Genomic instability is a key hallmark of cancer leading to tumour heterogeneity and therapeutic resistance. BRCA2 has a fundamental role in error-free DNA repair but also sustains genome integrity by promoting RAD51 nucleofilament formation at stalled replication forks. CDK2 phosphorylates BRCA2 (pS3291-BRCA2) to limit stabilizing contacts with polymerized RAD51; however, how replication stress modulates CDK2 activity and whether loss of pS3291-BRCA2 regulation results in genomic instability of tumours are not known. Here we demonstrate that the Hippo pathway kinase LATS1 interacts with CDK2 in response to genotoxic stress to constrain pS3291-BRCA2 and support RAD51 nucleofilaments, thereby maintaining genomic fidelity during replication stalling. We also show that LATS1 forms part of an ATR-mediated response to replication stress that requires the tumour suppressor RASSF1A. Importantly, perturbation of the ATR-RASSF1A-LATS1 signalling axis leads to genomic defects associated with loss of BRCA2 function and contributes to genomic instability and 'BRCA-ness' in lung cancers.
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Dafni-Eleftheria
authors.initials: DE
authors.lastname: Pefani
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Latusek
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pires
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Grawenda
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Yee
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Garth
authors.initials: G
authors.lastname: Hamilton
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.affiliation: Dunn School of Pathology, South Parks Road, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Esashi
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
authors.affiliation: CRUK/MRC Oxford Institute, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D020552:Comet Assay; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D006801:Humans; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008957:Models, Genetic; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C092745:LATS1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D051135:Rad51 Recombinase