SUMMARY
Georges Mer, Ph.D., and his team study how cells preserve genomic and epigenomic integrity. The group investigates how genome maintenance proteins, sometimes with RNA partners, assemble into large, dynamic complexes required for DNA repair and other chromatin-based processes. Current studies examine how posttranslational modifications regulate these assemblies and activate chromatin repair pathways. To pursue this work, the team combines complementary structural, biophysical and functional approaches. These include cryo-electron microscopy, nuclear magnetic resonance spectroscopy, X-ray crystallography, computational analyses, chemical manipulation of proteins, and biochemical and cell-based assays.
Focus areas
- Chromatin modifications in genome maintenance. The group studies how posttranslational modifications on nucleosomes and chromatin-associated proteins, including acetylation, ADP-ribosylation, lactylation, methylation, phosphorylation and ubiquitylation, regulate DNA repair. Ongoing projects focus on several proteins involved in DNA double-strand break repair, including the E3 ubiquitin ligases BRCA1-BARD1 and RNF168, and the DNA damage response mediator 53BP1.
- Structure and function of histone chaperones. Histone chaperones facilitate chromatin assembly and histone exchange during DNA repair, DNA replication and transcription. Across cell divisions, these processes help preserve chromatin organization and propagate chromatin-based epigenetic information, which is encoded in part by patterns of histone posttranslational modifications. Dr. Mer's team studies how histone chaperones form complexes with histones and how they modulate the activity of chromatin-modifying enzymes.
- Chemical approaches for structural studies. In support of the research areas outlined above, the lab develops chemical biology and protein engineering methods to capture and stabilize transient functional states of chromatin-associated complexes, enabling structural studies that help reveal molecular mechanisms.
- Structural dynamics and molecular recognition. Dr. Mer and colleagues use nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, calorimetry, molecular dynamics simulations and complementary biophysical approaches to investigate how conformational dynamics influence molecular recognition and protein function.
Significance to patient care
Dr. Mer's team studies the 3D shapes and movements of large molecules, including proteins that repair damaged DNA. This research helps scientists understand how these molecules work inside cells and may lead to new treatments for cancer and some disorders that affect the brain and nervous system. One current project focuses on creating small molecules to block the activity of a protein linked to a type of childhood cancer. The goal is to develop better treatments for this cancer.
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