Data from Multiple Isoforms of CDC25 Oppose ATM Activity to Maintain Cell Proliferation during Vertebrate Development

Abstract

<div>Abstract<p>The early development of vertebrate embryos is characterized by rapid cell proliferation necessary to support the embryo's growth. During this period, the embryo must maintain a balance between ongoing cell proliferation and mechanisms that arrest or delay the cell cycle to repair oxidative damage and other genotoxic stresses. The ataxia-telangiectasia mutated (ATM) kinase is a critical regulator of the response to DNA damage, acting through downstream effectors, such as p53 and checkpoint kinases (CHK) to mediate cell-cycle checkpoints in the presence of DNA damage. Mice and humans with inactivating mutations in ATM are viable but have increased susceptibility to cancers. The possible role of ATM in limiting cell proliferation in early embryos has not been fully defined. One target of ATM and CHKs is the Cdc25 phosphatase, which facilitates cell-cycle progression by removing inhibitory phosphates from cyclin-dependent kinases (CDK). We have identified a zebrafish mutant, <i>standstill</i>, with an inactivating mutation in <i>cdc25a</i>. Loss of <i>cdc25a</i> in the zebrafish leads to accumulation of cells in late G<sub>2</sub> phase. We find that the novel family member <i>cdc25d</i> is essential for early development in the absence of <i>cdc25a</i>, establishing for the first time that <i>cdc25d</i> is active <i>in vivo</i> in zebrafish. Surprisingly, we find that cell-cycle progression in <i>cdc25a</i> mutants can be rescued by chemical or genetic inhibition of ATM. Checkpoint activation in <i>cdc25a</i> mutants occurs despite the absence of increased DNA damage, highlighting the role of Cdc25 proteins to balance constitutive ATM activity during early embryonic development. <i>Mol Cancer Res; 10(11); 1451–61. ©2012 AACR</i>.</p></div>