NSF Award
2407334
This research project will advance our fundamental understanding of the molecular players that coordinate gene expression in the cell. Through studying their structure and function, further knowledge will be gained on some of the essential processes that they are involved in such as regulation of the cell cycle and DNA repair. In addition, this project will provide research opportunities for a number of underrepresented students at Eastern Michigan University, a diverse, primarily undergraduate institution that values student-centered and inclusive learning. Over a dozen undergraduate students will be closely trained in research by a strong, collaborative duo of PIs with extensive backgrounds in mentoring future scientists and professionals. An additional 24 students will also receive the benefits of research through the continuation of a CURE-grant proposal Biochemistry Lab writing-intensive course (CHEM 453W). This project will also expand and strengthen an existing High School Research Experience at EMU program, which provides research training during the summer to students in grades 9-12 from the local Greater Detroit community. <br/><br/>UHRF1 and UHRF2 are multi-domain epigenetic proteins that play critical roles in a variety of processes such as cell cycle regulation, DNA replication, DNA damage repair, and gene regulation. Both proteins contain two histone reader domains, called TTD and PHD, which recognize the post-translational modification (PTM) status on histone H3 to regulate DNA methylation/hydroxymethylation and gene expression. While these proteins share a high degree of sequence similarity, UHRF1 and UHRF2 have distinct and important nuclear functions that are mediated via chromatin interactions. Although much is known on the detailed histone binding properties by the TTD and PHD of UHRF1, there is still limited understanding of the structure and biological function of the same domains in UHRF2. This project will test if UHRF1 and UHRF2 exhibit distinct mode of histone binding and whether they can be specifically modulated by chemical probes. Elucidating the detailed differences between UHRF1 and UHRF2 will provide a greater understanding of the molecular requirements that dictate binding selectivity by these reader proteins. In addition, novel functionalities of UHRF2 may be uncovered by discovering new histone PTM binding partners and chemical probes that target UHRF2. An in-depth fundamental understanding of their structure, function, and ability to modulate their activities is an important step toward understanding the variety of critical cellular processes that UHRF1 and UHRF2 regulate.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
