Maintaining Genome Stability in Defiance of Mitotic DNA Damage

Abstract

The implementation of decisions affecting cell viability and proliferation is based on prompt detection of the issue to be addressed, formulation and transmission of a correct set of instructions and fidelity in the execution of orders. While the first and the last are purely mechanical processes relying on the faithful functioning of single proteins or macromolecular complexes (sensors and effectors), information is the real cue, with signal amplitude, duration, and frequency ultimately determining the type of response. The cellular response to DNA damage is no exception to the rule. In this review article we focus on DNA damage responses in G2 and Mitosis. First, we set the stage describing mitosis and the machineries in charge of assembling the apparatus responsible for chromosome alignment and segregation as well as the inputs that control its function (checkpoints). Next, we examine the type of issues that a cell approaching mitosis might face, presenting the impact of post-translational modifications (PTMs) on the correct and timely functioning of pathways correcting errors or damage before chromosome segregation. We conclude this essay with a perspective on the current status of mitotic signaling pathway inhibitors and their potential use in cancer therapy.

Keywords: DNA damage; cancer therapy; checkpoint; mitosis; phosphorylation; ubiquitylation.

Figure 1

DNA damage response in G2. Upon generation of double strand breaks (DSBs), ATM is recruited to DNA ends in a MRN-dependent manner. Phosphorylation of H2AX creates epitopes facilitating the recruitment of DNA damage signaling and repair factors in a manner that depends on PTMs such as ubiquitylation and sumoylation (see text for details and Bologna and Ferrari, 2013). Successful activation of ATM-dependent signals causes controlled resection of DNA ends that, in turn, trigger ATR-dependent pathways. The latter converge with the former on the master regulator of mitosis, CDK1, blocking its activity.

Figure 2

DNA damage response in mitosis. Irradiation of cells in antephase or in early prophase triggers a response that is independent of PI-3K-like kinases such as ATM but rather depends on the E3-ubiquitin ligase CHFR and the stress-response kinase p38MAPK. On the other hand, irradiation of cells in late prophase or in metaphase leads to a curtailed DNA damage response. Ultrafine anaphase bridges, caused by improper resolution of replication or recombination intermediates, are addressed by the coordinated action of the helicases PICH and BLM supported by RIF1 (see text for details).

Figure 3

Mitosis and its control by kinases, phosphatases and E3-ubiquitin ligases. Schematic representation of key controllers of the onset, transition and exit from mitosis with indication of the major drugs inhibiting their function. Kinases: blue; Phosphatases: green; E3-ubiquitin ligases: purple; Drugs: red.