Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.

Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens.

Proteins in the nutrient-sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage.

Checkpoint pathways regulate genomic integrity in part by blocking anaphase until all chromosomes have been completely replicated, repaired, and correctly aligned on the spindle. In Saccharomyces cerevisiae, DNA damage and mono-oriented or unattached kinetochores trigger checkpoint pathways that bifurcate to regulate both the metaphase to anaphase transition and mitotic exit. The sensor-associated kinase, Mec1, phosphorylates two downstream kinases, Chk1 and Rad53.

Targeting Rb mutant cancers by inactivating TSC2.

Retinoblastoma (Rb), a tumor suppressor gene, is inactivated in many types of cancer. However little is known about how the loss of Rb function can be targeted in cancer therapies. We have identified that inactivation of TSC2 in Rb mutant cancer cells will induce a synergistic cell death.

A role for Saccharomyces cerevisiae Chk1p in the response to replication blocks.

Replication blocks and DNA damage incurred during S phase activate the S-phase and intra-S-phase checkpoint responses, respectively, regulated by the Atrp and Chk1p checkpoint kinases in metazoans. In Saccharomyces cerevisiae, these checkpoints are regulated by the Atrp homologue Mec1p and the kinase Rad53p. A conserved role of these checkpoints is to block mitotic progression until DNA replication and repair are completed.

Stopped for repairs: a new role for nutrient sensing pathways?

In order to prevent division of damaged chromosomes, cells activate a checkpoint to inhibit mitotic progression in order to repair the damaged DNA. Upon detection of DNA damage two downstream checkpoint kinases, Chk1 and Rad53, are activated by the sensor kinase, Mec1, to block the metaphase to anaphase transition and mitotic exit, respectively. Recent data from studies with budding yeast suggested that the DNA damage checkpoint also enlists the cAMP dependent protein kinase (PKA) pathway, which is an integral part of the nutrient sensing mechanism in budding yeast, to inhibit mitosis in response to DNA damage.

The DNA damage checkpoint and PKA pathways converge on APC substrates and Cdc20 to regulate mitotic progression.

The conserved checkpoint kinases Chk1 and Rad53-Dun1 block the metaphase to anaphase transition by the phosphorylation and stabilization of securin, and block the mitotic exit network regulated by the Bfa1-Bub2 complex. However, both chk1 and rad53 mutants are able to exit from mitosis and initiate a new cell cycle, suggesting that both pathways have supporting functions in restraining anaphase and in blocking the inactivation of mitotic cyclin-Cdk1 complexes. Here we find that the cyclic-AMP-dependent protein kinase (PKA) pathway supports Chk1 in the regulation of mitosis by targeting the mitotic inducer Cdc20.