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  • Zoledronic Acid kinase A recent report has shown that


    A recent report has shown that C. elegans homozygous for a point mutation within the HORMA domain of HTP-1 (M127K), which disrupts its association with chromosome axes, displayed an extended zone of PLK-2 localization to PCs in response to asynapsis (Silva et al., 2014), which, as we show here, is a direct consequence of prolonged CHK-2 activity. This apparent feedback activity was attributed to a signal from the soluble nuclear pool of mutant HTP-1 protein. We note that this conclusion is inconsistent with our finding that mutating the six closure motifs in HTP-3, which prevents recruitment of HTP-1/2 (and HIM-3) to the chromosome axes, fully abrogates feedback regulation of CHK-2 (Figures 5 and 6). We also report that recruitment of a small amount of HTP-1 and/or HTP-2 to Zoledronic Acid kinase is sufficient to support feedback signaling. We therefore think it likely that feedback regulation in htp-1M127K mutants is mediated by HTP-2 along the chromosome axis rather than the mutant version of HTP-1 in the nucleoplasm. Because the formation of chromosome axes is a prerequisite for pairing, synapsis, and meiotic recombination, the HORMA domain proteins are ideally situated to monitor chromosomal events during meiotic prophase. This implies that the axis must undergo structural or biochemical changes during meiotic progression to sense and/or signal the status of meiotic events. Indeed, meiotic HORMA domain proteins in S. cerevisiae (Hop1) and mice (HORMAD1/2) are removed from synapsed axes by the AAA+ ATPase Pch2/Trip13 (Börner et al., 2008, Joshi et al., 2009, Roig et al., 2010, Wojtasz et al., 2009), suggesting a mechanism by which the checkpoint may be silenced in response to synapsis. However, the C. elegans ortholog of Pch2/Trip13, PCH-2, is largely dispensable for meiotic processes and is not required for axis remodeling (data not shown). Therefore, how the assembly of meiotic HORMA domain proteins is regulated dynamically to monitor chromosomal events and coordinate with meiotic progression remains to be determined. We recently confirmed that HIM-3 and HTP-1/2 are structurally very similar to Mad2 (Kim et al., 2014), raising the intriguing possibility that the meiotic HORMA domain proteins might undergo a Mad2-like dimerization and/or conformational change to mediate checkpoint signaling (De Antoni et al., 2005, Luo et al., 2004). However, mutating the αC helix of HTP-1 (F180A, K184A), corresponding to the dimerization interface of Mad2 (Mapelli et al., 2007), did not abrogate the feedback regulation (data not shown), indicating that this interface is not essential for signal transduction by HTP-1. Moreover, it is not yet known whether the meiotic HORMA proteins bind to downstream effectors through their HORMA domains in the same way that Mad2 transduces checkpoint signaling to the anaphase-promoting complex. Future identification of signaling effectors that directly regulate CHK-2 (e.g., phosphatases) will help to reveal how axis proteins collaborate to mediate the meiotic checkpoint.
    Experimental Procedures For full experimental details, see Supplemental Experimental Procedures.
    Author Contributions
    Upon DNA damage by ultraviolet light, radiation or cytotoxic drugs, the cellular response is to arrest the cell cycle at one of three checkpoints (G1/S, intra-S or G2/M) to either permit DNA repair or to initiate apoptosis. The serine/threonine checkpoint kinase, (CHK-1), regulates both the G2/M and intra-S checkpoints, and plays an important role in cell-cycle progression,, , , especially for -defective cancer cells. Since cell-cycle arrest is a mechanism by which tumor cells can overcome the damage induced by cytotoxic agents, abrogation of the G2/M checkpoint with novel small molecule compounds may increase the sensitivity of -deficient tumors to chemotherapy., Importantly, in contrast to many current therapies for cancer, this mechanism potentially carries with it only a low risk of toxicity against non-malignant cells, as CHK-1 inhibition is most effective in -defective cancer cells. Thus, a major advantage of CHK-1 inhibitors as a treatment for cancer is their selective activity in conjunction with cytotoxics, such as DNA-damaging reagents.