From Mitotic Spindle to DNA Damage Response

The Nguyen lab has deliberately explored new avenues of inquiry and consistently have obtained funding for their innovative ideas. For instance, the lab has refined and extended the functions of TPX2, a microtubule-associated protein well known for its roles in promoting spindle assembly and regulating mitosis (reviewed in Neumayer et al., Cellular and Molecular Life Sciences 2014, cover of the July issue).  During interphase, TPX2 preferentially resides in the nucleus but its nuclear role has remained elusive since its discovery 20 years ago. Furthermore, TPX2 displays over 40 in vivo putative phosphorylation sites but the majority of them have not been validated nor have they been functionally analyzed. The Nguyen lab made several key findings in these aspects:

- We found that TPX2 is phosphorylated at threonine 72 in human cells and this phosphorylation regulates its spindle assembly functions (Shim et al., Journal of Biological Chemistry 2015). A recent Cell publication entitled ‘SnapShot: Phosphoregulation of Mitosis’ mentioned the finding.

 

- We identified the first (and so far only) nuclear role of TPX2. We discovered that TPX2 plays a significant role in the amplification of the early DNA damage response (specifically that of gamma-H2AX signals) so essential to maintain genomic instability (Neumayer et al., Journal of Biological Chemistry 2012). We went on to unravel a crucial role for the protein in chromatin remodeling that may impact the establishment of this early DNA damage response (Neumayer al., PLoS ONE 2014).

 

Why are these findings important? TPX2 has been proposed as a biomarker and effector for cancer progression based on its elevated levels in numerous malignancies (lung, pancreas, ovary, bone, carcinomas, breast, cervix, etc.). In addition to these ‘cancer-type-specific’ analyses, TPX2 was also found to be overexpressed in 53 out of 193 (27 %) microarray assays that compared gene expression profiles of various cancers with their normal tissue counterpart. Furthermore, elevated levels of TPX2 were found to correlate best with the magnitude of chromosomal instability in a study that examined over 10,000 genes for such association. Our findings suggest that deregulation of TPX2 (by phosphorylation at Thr72 or through overexpression) may contribute to genomic instability in cancers by impairing spindle assembly and DNA damage response. All these new findings and concepts on TPX2 biology are discussed in a review article that made the cover of the July issue of Cellular and Molecular Life Sciences (Neumayer et al., Cellular and Molecular Life Sciences 2014).