MTG8 is a member of the MTG family of transcriptional co-repressors, first identified due to their frequent translocations in leukemia. It associates with other co-repressors, such as Bcl6, and histone deaceytlases (HDACs), such as HDAC3. Mtg8-null mice show a deletion of the mid-gut, which was attributed to a mesenchymal cell defect. Therefore, in preliminary work, isolated Mtg8-null murine embryonic fibroblasts (MEFs) were isolated and found to show a dramatic cell proliferation defect. Cell cycle analysis identified a G2/M phase delay, which could be traced to double strand DNA breaks that were associated with DNA replication. MTG8 has been identified as a candidate cancer gene by whole genome sequencing of human colorectal carcinomas (CRC) tumors as well as a study indicating that MTG8 mutations are associated with the development of CRC. Three mutations, R386W, R395W and A471V are cancer driver mutations and all three mutations are found in regions of protein:protein interactions, most notably near the binding sites of Bcl6 and HDAC3 both of which are known to affect genomic stability. I hypothesize that MTG8 interaction is required for genomic stability and that CRC- associated mutations of MTG8 affects its association with transcriptional regulators and/or genomic stability. In order to address this hypothesis, the following specific aims are proposed:
Specific Aim 1. Characterize the role of MTG8 in genomic stability Aim 1A. Define the contribution of MTG8 to DNA damage control.
Aim 1 B. Define the effects of CRC-related MTG8 mutations in vitro.
Specific Aim 2. Determine the biological role of CRC-related MTG8 mutations in vivo.
In Specific Aim 1, the role of wild type Mtg8 and CRC- associated mutations on genomic stability will be analyzed as well as the effect of the CRC-related mutations on protein: protein interactions.
In Specific Aim 2, mouse lines will be developed that contain the point mutations found in human CRCs. These mouse lines will then be characterized for the physiological role of MTG8 in genomic stability as well as how the mutations found in CRCs affect its functions.
The project entitled "The role of MTG8 in genomic stability and colorectal cancer development" addresses the effect of MTG8 mutations on colorectal cancer (CRC). Information from this project will help to further explain the biology of CRC and, more importantly, describe new targets for CRC-related therapies.