Editors' ChoiceCancer

At the Fork, LATS1 Chooses Stability

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Science Signaling  14 Oct 2014:
Vol. 7, Issue 347, pp. ec285
DOI: 10.1126/scisignal.aaa0427

A common feature of cancer is genomic instability, which is often caused by genotoxic damage or DNA replication stress. The DNA repair and tumor suppressor protein BRCA2 stabilizes the formation of RAD51 filaments along single-stranded DNA at stalled replication forks to promote their error-free resolution. One way that CDK2 (cyclin-dependent kinase 2) promotes cell cycle progression is by phosphorylating and inhibiting BRCA2. The Hippo pathway kinase LATS1 is activated by RASSF1A (Ras association domain family 1 isoform A) in response to DNA damage, promotes genomic stability, and is inactivated in several cancer types. Pefani et al. investigated the connections between LATS1 and BRCA2 in response to replication stress and DNA damage. Compared with wild-type counterparts, knockdown of LATS1 in U2OS cells or deletion of either Lats1 or Rassf1a in mouse embryonic fibroblasts (MEFs) increased the phosphorylation of BRCA2 and impaired the formation of RAD51 foci in response to ionizing radiation (IR)-induced DNA damage or hydroxyurea (HU)-induced stalled replication forks. LATS1- or RASSF1A-deficient cells also had increased HU-induced replication fork degradation and chromosomal aberrations, similar to previous observations of BRCA2-defective cells. Knockdown of YAP, a substrate of LATS1 in the Hippo pathway, had no effect on RAD51 foci formation. Expression of either wild-type or kinase-deficient LATS1 in Lats1-/- MEFs decreased BRCA2 phosphorylation and increased RAD51 foci formation, suggesting a kinase-independent function for LATS1. In response to either IR or HU, endogenous LATS1 and CDK2 formed a complex in U2OS cells, and LATS1 prevented the interaction of CDK2 with its substrates. Overexpression of a mutant LATS1 construct that could not interact with CDK2 impaired RAD51 foci formation in response to HU. LATS1 and CDK2 did not interact and chromosomal aberrations were increased in H1299 lung cancer cells that lack RASSF1A expression due to promoter methylation. Both LATS1-CDK2 interaction and chromosome stability was restored by expression of RASSF1A but not by a mutant that is not activated in response to DNA damage. Knocking down LATS1 prevented the chromosome-stabilizing effects of RASSF1A expression. RASSF1A promoter methylation correlated with genomic instability in a panel of lung adenocarcinoma patient tumors. Thus, the study identifies a function for LATS1 in promoting replication fork stability that is independent of its kinase function and its role in the Hippo pathway.

D. E. Pefani, R. Latusek, I. Pires, A. M. Grawenda, K. S.Yee, G. Hamilton, L. van der Weyden, F. Esashi, E. M. Hammond, E. O'Neill, RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. Nat. Cell Biol. 16, 962–971 (2014). [PubMed]

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