# FANCJ dependent pathways in replication stress

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $358,746

## Abstract

Project Summary:
Great progress has been made in uncovering the proteins and pathways that function in the replication stress
response. In particular, the hereditary breast cancer genes, as well as genes mutated in Fanconi anemia (FA)
function in the replication stress response. It is now understood that loss of their function in the replication
stress response contributes to the sensitivity of associated tumors to chemotherapies, such as cisplatin.
However, the distinct functions for the BRCA-FA proteins are largely unknown. Here, we propose to analyze
DNA replication fork dynamics, replisome components, and identify patient mutations that have specific defects
in the replication stress response.
To define how a cell transitions from defective to dysregulated replication, we have engineered cells
expressing different mutant versions of the BRCA1-associated FANCJ also mutated in breast/ovarian cancer
and FA. Similar to BRCA1, we have uncovered that FANCJ functions to protect replication forks from collapse.
We also found that this FANCJ fork protection function requires its direct interaction with the mismatch repair
(MMR) protein, MLH1. This finding provides insight as to why cells lacking the FANCJ-MLH1 interaction fail to
recover from replication stress. We have also identified putative gain-of-function FANCJ mutants, such as the
BRCA1-interaction defective mutant, that circumvent replication stress, keep forks intact, and confer hyper-
resistance to replication stress inducing agents. In Aim 1, we will seek to define how FANCJ interactions direct
DNA replication fork dynamics. Given that FANCJ localizes to replication forks, displaces proteins, and
unwinds DNA, we hypothesize that disrupted vs dysregulated replication will reflect not only changes in DNA
structures, but also the proteins found at DNA replication forks. In Aim 2, we will seek to determine how
FANCJ contributes to the composition of the replisome in both unchallenged and at stressed replication forks.
Replication stress induces changes to FANCJ protein interactions and post-translation modifications. Some of
these changes occur at sites we found to be mutated in cancer patients. In Aim 3, we will seek to generate
FANCJ mutants resistant to replication stress induced changes to uncover mechanisms regulating FANCJ
function that are lost in cancer. Collectively, by defining how cells succumb to- or survive- toxic DNA damage
that normally interferes with replication, we will gain insight towards mechanisms transitioning cells from
defective to dysregulated replication in cancer.
!

## Key facts

- **NIH application ID:** 10219989
- **Project number:** 5R01CA225018-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Sharon B Cantor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,746
- **Award type:** 5
- **Project period:** 2018-09-05 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219989

## Citation

> US National Institutes of Health, RePORTER application 10219989, FANCJ dependent pathways in replication stress (5R01CA225018-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219989. Licensed CC0.

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