Student Hosted Colloquia Seminar: Professor Gabe Lander, Scripps Research Institute
About the Seminar
CryoEM brings new mechanistic insights into double-stranded DNA break repair
DNA double-strand breaks occur in all human cells on a daily basis and must be repaired with high fidelity to minimize genomic instability. Deficiencies in the high-fidelity DNA repair pathways lead to overexpression of DNA polymerase theta, which identifies DNA microhomologies in 3’ single-stranded DNA overhangs and anneals them to initiate error-prone double-strand break repair. The resulting genomic instability is associated with numerous cancers, thereby making this polymerase an attractive therapeutic target. However, the molecular details of this error-prone mechanism are unknown. I will present cryo-electron microscopy structures of the polymerase theta helicase domain bound to microhomology-containing DNA, revealing DNA-induced rearrangements of the helicase that enable DNA repair. Our structures show that DNA-bound helicase dimers facilitate a microhomology search that positions 3’ single-stranded DNA ends in proximity to align complementary base pairs and anneal DNA microhomology. This study collectively defines the molecular determinants that enable the polymerase theta helicase domain to identify and pair DNA microhomologies to initiate mutagenic DNA repair, providing mechanistic insights into therapeutic targeting of these interactions.
About the Speaker
Gabe is a Professor in the Department of Structural and Computational Biology at Scripps Research. His group’s research is focused on combining cryo-EM methodologies with biochemical, biophysical, and computational techniques to produce detailed mechanistic descriptions of the molecular processes that underlie cellular homeostasis and stress-response pathways. Gabe’s studies challenge existing paradigms, with a notable track record of overturning existing long-standing myths in both cryo-EM as well as biology. The pioneering methodological avenues of research established by Gabe’s group have enabled detailed examination of molecular assemblies ranging widely in size and shape to understand their architectures, the conformational landscapes that are responsible for molecular function, and how these landscapes are influenced by small molecule ligands. These research strategies are being used to explore and define the molecular bases of human disease, including heart disease and cancers. Gabe received a B.S. in biochemistry and computer science from Binghamton University, and subsequently carried out his graduate studies at Scripps Research under the joint supervision of Bridget Carragher, Clint Potter, and Jack Johnson. Gabe performed his postdoctoral work in the lab of Eva Nogales at UC Berkeley, where he collaborated closely with Drs. Andreas Martin and Jennifer Doudna. He joined Scripps as an Assistant Professor in 2013, and was promoted to Professor in 2019. Over his academic career, Gabe has received numerous recognitions and awards, which include the Damon Runyon Dale F. Frey award, an NIH Innovator Award, Searle and Pew Scholarships, an Amgen Young Investigator Award, and a Protein Science Young Investigator from the Protein Society.