# Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)

> **NIH NIH R35** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $714,970

## Abstract

PROJECT SUMMARY/ABSTRACT
Cancer is linked to almost every human DNA repair (DR) pathway. Genomic instability, which results
from DR defects, is a cancer hallmark. Thus, DNA damaging cancer therapies are widely used and
are often successful. Yet, the effects of DNA damage depend on poorly understood DR complexes
that are also targets for advanced treatments, e.g. PARP inhibitors that rely on a synthetic lethality
(SL) relationship between PARP and BRCA proteins. Although effective initially, these treatments
often later fail due to various means of resistance developed in tumors. Thus, better strategies are
urgently required to delay or avoid resistance by identifying new SL partners. This revised MANTIS-
DRC R35 application will focus on the BRCA paradox (whereby BRCA-defective tumor cells survive
yet BRCA inactivation causes cell and embryonic lethality) with implications for future efforts to
modulate the DNA damage response to harness the abscopal effect (a paradox whereby ionizing
radiation is immunosuppressive yet can activate an immune response to kill tumors distant from the
radiation site). We hypothesize that answers to both the 'BRCA paradox' and the ‘abscopal paradox’
lie in changes to DNA damage response that will aid in identifying strategies to tackle resistance.
Based upon his NCI-funded experience, Prof. Tainer is poised to build program efforts to efficiently
define and test these DR changes that will inform: 1) BRCA essentiality in most cells and SL in
tumors and 2) strategies to control the abscopal effect. This work will thus leverage and apply
Tainer’s seminal contributions in integrating crystal structures with X-ray scattering to define
conformations and assemblies in solution that link structures to phenotypes. Specifically, we will focus
on defining a largely enigmatic BRCA1 interactome by producing atomic-resolution structural
information and identifying new BRCA1 SL partners: these will be key proteins and interfaces
regulating DR pathways (and potentially capable of inducing an abscopal response) that are difficult
to overcome via resistance pathways. To elucidate how DR complexes orchestrate cellular processes
on DNA, we will integrate structure and imaging to map their spatial distribution and measure their
temporal dynamics with systematic and comprehensive analyses. Rather than correlating large data
sets, we will rigorously merge suitable data sets via tested Bayesian approaches for integrating data
with maximum likelihood weighting according to the relative confidence in each measurement.
Leveraging cutting-edge clinical information at MD Anderson will enable testing relevance and impact
of our predictions by comparisons with results in patient databases. Anticipated collective results will
produce quantitative, objective and mechanistic data to combine measurements from molecules to
cells, to design dissection-of-function mutations and inhibitor tools, and to predict biological outcomes.

## Key facts

- **NIH application ID:** 9996516
- **Project number:** 5R35CA220430-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** John A. Tainer
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $714,970
- **Award type:** 5
- **Project period:** 2018-09-13 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996516

## Citation

> US National Institutes of Health, RePORTER application 9996516, Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC) (5R35CA220430-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996516. Licensed CC0.

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