# Cellular responses to DNA replication stress

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $333,638

## Abstract

PROJECT SUMMARY
Genomic instabilities drive the progression of cancer, aging, and other human diseases. The integrity of our
genome is especially at risk while it is being replicated, as replication forks often encounter obstacles to their
progression, including DNA lesions, hard-to-replicate sequences, transcription intermediates, or protein-DNA
complexes. These encounters often result in DNA breaks, gross chromosomal rearrangements and
aneuploidy, which are key events in cancer initiation. The proper repair of stalled or collapsed replication forks
through homologous recombination (HR)-based mechanisms plays a major role in preventing replication
stress-induced genomic instabilities and many mutations in components of the HR machinery have been
associated with cancer predisposition. In the absence of an intact HR-machinery, error-prone mechanisms
such as non-homologous end joining (NHEJ) tend to become hyper-utilized, leading to extensive genomic
instability. The regulatory basis of the recruitment of HR and NHEJ factors to DNA lesions is therefore of
central interest to genome biology and cancer research, not only for explaining the mechanisms of
tumorigenesis, but also for providing promising avenues for cancer therapy, as recently demonstrated for
PARP inhibitors that are now approved for treatment of ovarian cancer patients with BRCA1 mutations in
Europe and the US. This proposal will investigate a new mechanism for regulation of recombinational DNA
repair and repair pathway choice. The central hypothesis is that the evolutionarily conserved scaffolding
protein TopBP1 plays a central, yet largely unexplored, role in the control of HR-mediated repair and DNA
repair pathway choice. Utilizing biochemical, proteomic and genetic approaches in yeast, human cell lines and
genome-edited mice, we will define the molecular mechanism by which TopBP1 and its yeast ortholog Dpb11
control DNA repair. Our studies will provide unparalleled molecular understanding of how the action of key HR
and NHEJ factors are coordinated and will reveal how signaling networks integrate the control of DNA
replication, checkpoint signaling and DNA repair. Proposed experiments will reveal novel mechanisms of repair
pathway choice and recombinational repair that are crucial to suppress genomic instability and cancer.
Generated outcomes will have implications in the study of tumorigenesis caused by dysfunctions in HR repair
and should provide new rationale for therapy.

## Key facts

- **NIH application ID:** 9923716
- **Project number:** 5R01GM097272-09
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Marcus Smolka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $333,638
- **Award type:** 5
- **Project period:** 2011-09-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923716

## Citation

> US National Institutes of Health, RePORTER application 9923716, Cellular responses to DNA replication stress (5R01GM097272-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9923716. Licensed CC0.

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