Novel insights into maintaining genomic integrity: Wee1 regulating Mus81/Eme1

Different external and internal agents can cause genomic alterations that trigger a variety of mechanisms allowing the cell to repair the injuries or avoid its cell cycle progression. The correct functioning of these pathways, generally called DNA Damage Response (DDR) is essential for maintaining genome integrity and for preventing the development of diseases associated with genomic instability [1].The phosphatidylinositol 3-kinase like kinases (PIKKs) ATM and ATR are central kinases in the DDR. ATM responds to DNA double strand breaks (DSBs), while ATR is activated in response to a wider variety of DNA lesions such as UV-induced damage, replication stress and DSBs. After DNA damage, ATR and ATM, with the help of other DDR proteins, phosphorylate and thereby activate the two effector kinases Chk1 and Chk2, respectively, which are essential to transmit the upstream signal to the downstream proteins [2].DNA replication can be a risky process and when replication is compromised the DNA is more vulnerable to suffer breakages [3]. Under these conditions, DNA secondary structures such as stalled replication forks are formed, which triggers a DDR that stabilizes the fork thereby avoiding replication fork collapse. Besides DDR proteins, specific enzymatic activities are required, for example the Mus81/Eme1 dimer, to revert stalled replication forks. This heterodimeric complex is a structure-specific endonuclease, where Mus81 is the catalytic subunit and Eme1 the regulatory factor [4]. This enzyme is involved in the cleavage of stalled and blocked replication fork by introducing DSBs to allow the replication recovery [5,6].Wee1 is a serine/threonine and tyrosine kinase that was first identified as a Cyclin-dependent kinase (Cdk) regulator [7,8]. Wee1 protein levels are highly regulated during the cell cycle. Wee1 activity and levels are high during S and G2 phases, when Wee1 is able to inhibit Cdks by phosphorylating them at tyrosine 15 and threonine 14 [9]. During the G2/M