Safeguarding genome stability: RASSF1A tumor suppressor regulates BRCA2 at stalled forks.
While it has been widely established that defective fork restart after exposure to stress results in increased genomic instability, the importance of fork protection during stalling for safeguarding genomic integrity has recently been fully appreciated. BRCA2, Breast tumor suppressor, has dual functionality promoting not only DNA repair but also preventing DNA lesions at stalled forks. In response to replication stress, BRCA2 recruits RAD51 onto nascent DNA at stalled forks, protecting nascent DNA from nucleolitic cleavage. Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity. Recently we uncovered how the core Hippo pathway components RASSF1A, MST2 and LATS1 regulate CDK2 activity towards BRCA2, in response to fork stalling. In complex with LATS1, CDK2 exhibits reduced kinase activity which results in low levels of pBRCA2-S3291 and stable RAD51 filaments protecting nascent DNA from MRE11 cleavage. In the absence of the RASSF1A/MST2/LATS1/CDK2 pathway increased resection of newly synthesized DNA leads to chromosomal instability and malignant transformation. This function of RASSF1A in stalled replication fork protection adds to the role of RASSF1A as a tumor suppressor and builds up evidence for RASSF1A status and its prognostic and predictive value in cancer.
a CRUK/MRC Oxford Institute; Department of Oncology; University of Oxford ; Oxford , UK.
Dafni Eleftheria
DE
Pefani
Eric
E
O'Neill
D024682:BRCA2 Protein / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology*; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
D024682:BRCA2 Protein; D051357:Cyclin-Dependent Kinase 2; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; C551750:BRCA2 protein, human; C411762:RASSF1 protein, human; C092745:LATS1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases; C495894:CDK2 protein, human