# Mechanisms of Endogenous DNA Damage Promotion

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $676,743

## Abstract

Mechanisms of Endogenous DNA Damage Promotion
Identification of the oncogenic mechanisms underlying cancer-promoting mutations remains a critical bottleneck
in translation of discovered cancer-gene identities into effective anti-cancer strategies. Furthermore, strong
correlations of Alzheimer’s disease (AD) with cancers indicate that these mechanisms also underlie AD. Their
identification may allow fundamentally new AD pre-disease biomarkers, diagnostic, preventative and possibly
therapeutic strategies. The goal of this multi-PI project is to leverage the team’s discovery in Escherichia coli,
and its immediate translation to human homologs, of large, diverse, conserved networks of proteins that promote
endogenous DNA damage and genome instability when overproduced—the DNA “Damage-up” Proteins (DDPs).
DDP identities and mechanisms discovered indicate that many known and unknown overproduced oncoproteins
are likely to constitute oncogenic and AD-associated mechanisms in which pathologies arise from destabilization
of genomes rather than via the proteins’ other specific cell-biological functions. A network of E. coli DDPs
promote endogenous DNA damage and mutation when overproduced, modeling many overproduction
oncoproteins. The human homologs are highly enriched among known cancer driving genes, and their RNAs in
cancers predict heavy tumor mutation loads and poor patient outcomes. 46% of human homologs sampled
promote DNA damage and mutagenesis when overproduced in human cells, demonstrating the power of the E.
coli platform for predicting human functions. Unlike genome instability and cancer caused by DNA-repair gene
loss-of-function mutations, DDPs promote genome instability as gain-of-function alterations (overproduction),
and so potentially can be drugged. DDPs defy previous cancer-gene/protein functional classes because they
destabilize genomes but are not DNA-repair genes that suppress mutation rate, but instead are instigators of
endogenous DNA damage and genome instability via mechanisms previously poorly defined. This project is
aimed at revealing fundamental conserved mechanisms and consequences of endogenous DNA-damage
promotion by DDPs using the E. coli model to guide cancer-protein function discovery in human cells. Because
the DDPs and their activites are a new and innovative conceptual paradigm, we expect results of this project to
re-direct many ongoing efforts in cancer prevention, diagnosis, and treatment. Because vast numbers and kinds
of proteins are implicated, and cancer is strongly correlated with AD, increased endogenous DNA damage may
be a widespread biomarker for cancer and AD susceptibility.

## Key facts

- **NIH application ID:** 10013865
- **Project number:** 1R01CA250905-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Kyle M Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $676,743
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013865

## Citation

> US National Institutes of Health, RePORTER application 10013865, Mechanisms of Endogenous DNA Damage Promotion (1R01CA250905-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10013865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*