# Pathway Choice of DNA Double-Strand Break Repair

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $361,898

## Abstract

PROJECT SUMMARY/ABSTRACT
A large number of DNA lesions occur within a cell each day jeopardizing the integrity of the genome, of which
DNA double strand breaks (DSBs) are the most toxic lesions. Unrepaired or misrepaired DSBs can result in
senescence, inducted apoptosis, or chromosomal aberrations, including translocations and deletions. These
chromosomal aberrations can lead to genomic instability and tumorigenesis. To counter DSBs, organisms
have evolved a complex mechanism of DNA damage response that includes recognition of the broken DNA
molecule, cellular signaling including modulation of the cell cycle via checkpoints, and ultimately the repair of
the DNA lesion. Two prominent pathways mediate the repair of DSBs in mammalian cells: homologous
recombination (HR) and non-homologous end-joining (NHEJ). Although much work has been performed to
identify and characterize the factors of each DSB repair pathway, important questions regarding cross-talk
amongst pathways remain unresolved. These include elucidating factors that initially bind to the DSB ends and
stabilize them, whether these factors influence recruitment of downstream factors and whether these factors
modulate pathway choice/switching between NHEJ and HR for the repair of DSBs. In this study, we will take a
novel “Ku-centric” view of DSB repair pathway choice in mammalian systems, which challenges the paradigm
established in yeast models. We hypothesize that Ku binds to DSBs in all cell cycle phases to protect DNA
ends, and that phosphorylation-mediated dissociation of Ku from DSBs is one of the key mechanisms
responsible for modulating pathway choice between NHEJ and HR in S phase. Furthermore, we postulate that
dysregulation of this process will result in genomic instability and increased susceptibility to tumorigenesis and
most importantly, will provide an insight into the etiology of spontaneous tumors. To test this hypothesis, we
propose the following specific aims: 1) To determine the kinase(s) responsible for Ku70 phosphorylation and
the mechanism mediating Ku dissociation from DSBs in response to DNA double-strand breaks; 2) To test the
hypothesis that Ku phosphorylation is essential for homologous recombination repair (HR), DNA damage
response (DDR), and maintenance of genome stability in human cells; and 3) To test the hypothesis that Ku
phosphorylation-dead mutations cause genome instability and lead to tumorigenicity in mouse model. Finally,
since a number of human genetic diseases and initiation of carcinogenesis are directly associated with
impaired or misrepaired DNA lesions and mutations in DSB repair genes, we believe basic mechanistic
insights into DSB repair mechanisms and regulation of DSB repair pathway choice could lead to the
identification of possible drug targets, which would ultimately translate into clinical benefits.

## Key facts

- **NIH application ID:** 10003146
- **Project number:** 5R01CA162804-09
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Anthony J Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,898
- **Award type:** 5
- **Project period:** 2012-04-09 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003146

## Citation

> US National Institutes of Health, RePORTER application 10003146, Pathway Choice of DNA Double-Strand Break Repair (5R01CA162804-09). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10003146. Licensed CC0.

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