New mechanisms for chromosomal instability under cell division
Aneuploidy results from an unequal distribution of sister chromatids during cell division and plays a significant role in tumorigenesis in somatic mitotic cells. Abnormal chromosome numbers are widely found in malignant tumor cells and it is known that aneuploidy resulting from chromosomal instability (CIN) precedes and even causes cell transformation.
We and others have previously shown that a range of fundamental nuclear processes (replication, transcription, mitotic chromosome condensation) are regulated via tethering of signaling molecules and chromatin modifiers by the nuclear A-kinase anchoring proteinAKAP95. Preliminary evidence we obtained suggests a role for AKAP95 in regulation of genetic material integrity by promoting correct chromosome segregation in mitosis. We hypothesize that AKAP95 constitutes a relay platform processing information from various signaling pathways to the genome and to chromatin regulators with important roles in mitosis.
Our project proposes to establish the role of AKAP95 in proper chromosome segregation during cell division and in transcriptional reactivation after completion of mitosis. Elaborating on the role of AKAP95 in the regulation of proper chromosome segregation in mitosis, we plan to examine whether AKAP95 functionally interacts with the nuclear pore complex protein TPR (which we find associated to AKAP95 and for which a similar role in regulation of genetic material integrity has been shown) in this pathway.
We would also like to explore a role for AKAP95 in bookmarking cancer-relevant genes during mitosis that would affect transcriptional reactivation following mitosis completion.
Our results are expected to provide novel insights in the function of AKAPs in mitosis and demonstrate an implication of AKAP95 in two current science topics: chromosomal instability and gene bookmarking. Importantly, we will contribute to the molecular identification of components involved in these two well-described mitotic events of fundamental importance but which remain largely uncharacterized mechanistically.
Finally, the mechanisms leading to CIN should allow design of new strategies in anti-cancer therapeutics. Chromosomal instability (CIN) has been associated with poor prognosis in a wide variety of cancers. Despite the prevalence and clinical relevance of CIN, a consistent basis for its underlying mechanisms is lacking. Yet, its frequency, clinical significance and restriction to neoplastic tissue suggest CIN could represent an attractive therapeutic target. Our proposal to discover mechanisms leading to CIN is thus of high relevance and benefit to society to design new strategies in anti-cancer therapeutics.
This project is supported by the Czech-Norwegian Research Programme (Project 7F14369: "NuArch: nuclear architecture in the regulation of autophagy, DNA repair and gene expression") and Kreftforeningen.
For more information concerning our research area and the methodologies we typically use, please see: www.collaslab.com.