# Structural Biology Studies of a Large DNA Repair Complex

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2024 · $403,977

## Abstract

Our research program aims to understand the relationship between macromolecular structure, dynamics,
and function, with a particular focus on large nucleic acid binding proteins. To this end, we use sensitive
methyl-based solution-state nuclear magnetic resonance (NMR) spectroscopy, which is capable of probing
the structure and dynamics of proteins and their complexes with masses >1 MDa. We couple NMR
spectroscopy with other powerful biophysical techniques to probe structure and dynamics and then employ
biochemical and in vivo activity assays to better understand function. Our strategy relies on rationally
designing mutations to disrupt specific interactions within the protein/protein complex as well as naturally
occurring mutations found in disease states to ‘break’ the structure/dynamics/function relationship in order
to piece together how the protein complex works. Currently, our primary focus is the MRE11-RAD50-
NBS1/Xrs2 (MRN/X) protein complex, which plays a central role in the DNA double strand break (DSB)
repair response. The MRN/X complex is essential for detecting and repairing DNA DSB breaks, as well as
for signaling their presence to the rest of the DNA DSB response. Additionally, the MRN/X complex has
roles in DNA replication and telomere maintenance. Not surprisingly then, mutations in MRN/X have been
found in many types of cancer and in diseases characterized by immunodeficiency, neuronal and cerebral
degeneration, a sensitivity to ionizing radiation, and oncogenesis. To fully understand how the MRN/X
complex performs all of its functions, it is necessary to determine structural models in the absence and
presence of its various substrates. Indeed, structural biology techniques, including NMR spectroscopy, have
been used to study the MRN/X complex and have revealed a diverse set of structures. Though insightful,
these models have raised more questions about how the structures are specifically involved in MRN/X
function, the relative populations of these heterogeneous structures in solution, the kinetics for the
interconversion between these structures, and short and long-range allosteric communication within them.
In the next five years, our goal is to bring clarity to each of these questions by applying our comprehensive
biophysical and biochemical research strategy. In general, we strive to better understand how protein
complexes use a diverse set of structures and biochemical activities to perform and coordinate complex
biological functions. These proposed studies will provide an unparalleled view into MRN/X function in DNA
DSB repair.

## Key facts

- **NIH application ID:** 10764668
- **Project number:** 2R35GM128906-06
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Michael Parker Latham
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,977
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764668

## Citation

> US National Institutes of Health, RePORTER application 10764668, Structural Biology Studies of a Large DNA Repair Complex (2R35GM128906-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10764668. Licensed CC0.

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