# Understanding the mechanistic role of genome stability pathways in regulating cell homeostasis

> **NIH NIH R35** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $423,750

## Abstract

PROJECT SUMMARY/ABSTRACT
To preserve genomic integrity and maintain homeostasis, cells in our body must effectively respond to both
exogenous and endogenous sources of DNA damage. How cellular DNA damage contribute to human disease,
including neurological disorders and cancer, is a fundamental area of research. For the past thirteen years, my
lab has been focused on studies related to the mechanistic basis of genomic instability. The goal of this MIRA
application is to address critical gaps in our understanding of genome stability pathways and how they are
differentially utilized in dividing versus non-dividing cells for the proper maintenance of cellular homeostasis. By
relaying external information from the cell periphery to the nucleus, cell surface receptor tyrosine kinases (RTKs)
respond to growth factors via PI3-kinase (PI3K)-AKT signaling to regulate gene expression and thereby promote
growth and/or survival. Similarly, DNA damage threatens genome integrity and upon detection within the nucleus
elicits DNA damage response (DDR) signaling to aid in DNA repair and cell cycle checkpoints. For our research
program, we will address unique mechanisms related to how key DDR factors contribute to extracellular growth
factor signaling crosstalk in dividing and non-dividing cells. To establish these mechanisms, we will utilize an
array of innovative experimental approaches including genome-wide sequencing, proximity ligation proteomics,
super-resolution microscopy and single-molecule tracking in live cells. We will test the hypothesis that the DDR
should be viewed as a broader, stress-responsive network linking nuclear and cytoplasmic effectors to maintain
physiological homeostasis through intersecting with growth factor signaling pathways. How this is achieved
mechanistically will be a major focus of this application. The second project involves addressing how genotoxic
stress in dividing cells impacts DNA replication dynamics and to elucidate novel molecular players that regulate
replication fork recovery. Based on our innovative technique called Okazaki fragment sequencing (OK-seq), we
are able to directly quantify the efficiency of replication fork initiation and termination at specific sites throughout
the genome. Using this technique, we will expand our analysis to understand how genotoxic insults and DNA
repair deficiencies contribute to site-specific replication fork-mediated DNA breaks using genome-wide analysis.
Deciphering the mechanisms that contribute to replication-associated genomic instability may provide new
avenues for targeted cancer treatment.

## Key facts

- **NIH application ID:** 10086651
- **Project number:** 1R35GM139610-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Tony Tung Huang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086651

## Citation

> US National Institutes of Health, RePORTER application 10086651, Understanding the mechanistic role of genome stability pathways in regulating cell homeostasis (1R35GM139610-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086651. Licensed CC0.

---

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