CDC5 Inhibits the Hyperphosphorylation of the Checkpoint Kinase Rad53, Leading to Checkpoint Adaptation

Abstract

The mechanistic role of the yeast kinase CDC5, in allowing cells to adapt to the presence of irreparable DNA damage and continue to divide, is revealed.

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

“…In light of this, it is interesting to note that the CDC5 gene is not haploinsufficient for normal cell proliferation in yeast, which suggests that a 50 % reduction in the levels of this kinase is insufficient to delay cell cycle progression in the absence of DNA damage. In contrast, it has been shown that heterozygous mutations in CDC5 can affect the adaptation response, which suggests that the process responds quantitatively to Cdc5 activity in cells (Vidanes et al 2010). It is however conceivable that a change in Cdc5 substrate specificity might also be important for the initiation of the adaptation response.…”

“…It is difficult to determine whether the phosphatases that normally inactivate Rad53 during checkpoint recovery, PP2C and PP4 (Guillemain et al 2007;Leroy et al 2003;O'Neill et al 2007), are also involved in adaptation since mutants in these proteins are defective in both processes. Interestingly, it has been suggested that inactivation of Rad53 during adaptation could be mediated by Cdc5 phosphorylation-induced inhibition of Rad53 (Schleker et al 2010;Vidanes et al 2010) (Fig. 1c).…”

“…This is usually detected by monitoring cell morphology (e.g., yeast budding or microcolony formation on solid medium; Lee et al 1998;Sandell and Zakian 1993;Toczyski et al 1997) or the appearance of changes in cell cycle status (e.g., passage from interphase to mitosis, completion of DNA replication, appearance of chromosome condensation; Kubara et al 2012;Syljuasen et al 2006;Yoo et al 2004). At the molecular level, adaptation is also associated with silencing of the DNA damage signaling machinery (e.g., dephosphorylation of checkpoint effectors; Donnianni et al 2010;Pellicioli et al 2001;Vidanes et al 2010), while markers of DNA damage persist. Ultimately, cellular adaptation to DNA damage will allow cells to proliferate under conditions that might otherwise block cell cycle progression or cause cell death.…”

“…This is due to the fact that elimination or overexpression of effectors of either one of these processes is predicted to yield identical phenotypes (i.e., permanent arrest after DNA damage, or cell cycle re-entry, respectively; Donnianni et al 2010;Leroy et al 2003;Vidanes et al 2010;Vaze et al 2002). Indeed, it would be surprising that mutants unable to recover from past DNA damage would not also be defective in adapting to the presence of permanent damage (as an indirect consequence of their recovery defect).…”

“…If Bfa1 is not the key or sole target of Cdc5 in the adaptation response, then what is its effector in this process? A candidate-based screen has eliminated a number of key phosphatases normally involved in cell cycle progression and checkpoint recovery (Vidanes et al 2010). In contrast, a number of DNA repair and checkpoint factors, including Sae2/CtIP, Mus81-Mms4, and Rad51 are known or proposed substrates for Cdc5 in the DNA damage response (Donnianni et al 2010;Gallo-Fernandez et al 2012;Matos et al 2011Matos et al , 2013Schwartz et al 2012;Yata et al 2012).…”