These proteins also share the ability to bind histone H2A (or H2AX in mammals) that has been phosphorylated the ATM/ATR family of master DNA damage response checkpoint kinases (Li et al. 2012; Manke et al. 2003; Williams et al. 2010; Yan et al. 2011).
These findings integrate SETD2 into the p53 regulatory network and provide a reasonable explanation for the intriguing observation that inactivation of this master regulator of cell cycle checkpoints in ccRCC is rarely caused by mutations in TP53 (Gurova et al., 2004; Dalgliesh et al., 2010; Sato et al., 2013).
Wee1 kinase activity therefore serves as a master regulator of cell cycle checkpoints by inactivating the CDK1-Cyclin B and CDK2-Cyclin E complexes until it can be assured that genomic integrity will be maintained and that the appropriate genetic information will be passed on to daughter cells.
In particular, p53, p63 and ATM presumably act to reinforce germline integrity by apoptosis, of which p53 is the master regulator controlling DNA-damage and checkpoint failure-induced apoptosis in many cell types (reviewed by Meulmeester and Jochemsen, 2008).
Checkpoint activation is controlled by two master kinases, ATM and ATR.
The tumor suppressor p53 is a direct substrate of ATM kinase (Canman et al., 1998) and is a master effector of the DNA damage cell cycle checkpoints (Sperka et al., 2012).
Chk1 promotes the DNA damage checkpoint pathway while Cds1 acts as the master kinase for activation of the replication checkpoint to phosphorylate Cdc25, thereby inhibiting the Cdc2 (Cdkinasenand and facilitating DNA repair and recombination pathways [7], [8], [9], [10], [11], [12], [13].
The DNA damage checkpoint works together with cyclin-dependent kinases (CDKs), master regulators of cell cycle progression, to avoid HR-mediated genetinstabilityithroughugh post-translational modifications of recombination proteins.
The Russian master and Soviet dissident Mstislav Rostropovich brought the Cello Suites to Checkpoint Charlie as the Berlin Wall fell in November 1989.
