# Genome Integrity Through the Cell Cycle in Homeostasis and Cancer

> **NIH NIH F99** · ROCKEFELLER UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary/Abstract
The stability of the mammalian genome depends on a remarkable toolkit of surveillance, repair,
signaling, and checkpoint mechanisms. Mutations in the DNA itself, or corruptions in many of
these genome integrity mechanisms, can result in disease including cancer. Given the
importance of mutation and cell division in tumorigenesis, two central pathways in genome
integrity are the DNA damage response, and the cell division cycle. A more complete
understanding of these pathways is crucial to our knowledge of normal cellular development in
homeostasis, stem cell biology, the etiology of cancers, as well as for technical applications like
gene targeting. This project seeks to tackle outstanding problems in these fields in order to
elucidate fundamental molecular cell biology mechanisms that can improve therapeutic
outcomes in cancer.
 The F99 phase is focused on double-strand break (DSB) repair and the control of end
resection, a critical molecular ‘choice’ of whether to repair a DSB by blunt end-joining or by
homologous recombination. I revealed novel mechanistic insights about the protein controlling
this choice, 53BP1, findings relevant to the treatment of BRCA1-deficient cancers with PARP1
inhibitors. We found that—instead of blocking end resection as was generally thought—53BP1
recruits polymerase alpha to counteract resection by fill-in synthesis of the resected DSB. In the
remainder of the dissertation work, I will explore how BRCA1 and 53BP1 regulate resection and
fill-in synthesis in light of this new model. I will also gain the necessary experience and exposure
scientifically and professionally to transition to a cancer-focused postdoc in a stellar lab.
 For the K00 phase, I will shift my focus and approaches to study mechanisms preserving
genome integrity in the critical window of mitosis, where diverse chromatin biology pathways
converge. I plan to learn and implement high throughput screens, computational analysis of
larger, statistically-powerful data sets, as well as in vivo modeling in the mouse, and analysis of
sequencing data from human tumor samples. These new approaches, coupled with my already
strong background in genetics, microscopy, and biochemistry, will allow me to address the most
pressing and challenging issues in genome integrity and cancer biology today. With the aid of
this award, I intend to continue my research contribution and gain experience in order to
become a leader of my own cancer-focused lab and a leader in the field of genome integrity.

## Key facts

- **NIH application ID:** 10015248
- **Project number:** 5F99CA245720-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Zachary Kenneth Mirman
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-09-13 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015248

## Citation

> US National Institutes of Health, RePORTER application 10015248, Genome Integrity Through the Cell Cycle in Homeostasis and Cancer (5F99CA245720-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10015248. Licensed CC0.

---

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