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. Author manuscript; available in PMC: 2016 Jan 1.
Published in final edited form as: Mutat Res Rev Mutat Res. 2014 Oct 22;763:168–180. doi: 10.1016/j.mrrev.2014.10.003

Figure 2. Proper Chk1 activation and function require a dynamic, tightly regulated balance of its subcellular localization.

Figure 2

A fork initiating checkpoint signaling is shown (for simplification one of the parental strands is not shown). Under unperturbed conditions, a fraction of Chk1 is recruited to chromatin, in part through its C-terminal PIP motif that binds PCNA. ATR then phosphorylates Chk1 on serines 317 and 345, and ATR-activated Chk1 engages in auto-phosphorylation of serine 296 (represented as the third P in the soluble Chk1). Upon genotoxic stress, at least two mechanisms contribute to Chk1 accumulation at sites of DNA damage: a) cytoplasmic, p90 RSK-dependent phosphorylation of S280 serves to accumulate Chk1 in the nucleus (whether this modification is lost or kept upon nuclear entry is not known); b) the N-terminal PbR motif in Chk1 binds PAR chains synthetized by and attached to PARP1. As a result of these two mechanisms and of increased loading of ATR onto stalled forks (Fig. 1), more Chk1 molecules get activated under perturbed in comparison to unperturbed conditions. Physiologically active and stress-activated Chk1 phosphorylate proteins both at chromatin and in the nucleoplasm (see text for details).