# Proteolytic control of DNA interstrand cross-link repair and genome integrity

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2022 · $361,897

## Abstract

PROJECT SUMMARY
 Genome instability caused by incorrect DNA repair system is a major driver for tumorigenesis. Our long-
term goal is to understand how cellular proteolysis controls the pathway responsible for repairing DNA
damage, thereby preserving the integrity of the genome. Since homeostasis of DNA repair factors is critical for
the activity of DNA repair, elucidating underlying mechanisms for the ubiquitin-proteolytic pathway in DNA
repair is essential for understanding the etiology of cancer when it is derailed. We are interested in the
mechanisms that link proteolysis to signaling of the Fanconi anemia (FA) DNA repair pathway, which deals
with DNA interstrand cross-links (ICL) encountered during DNA replication. Its defects lead to a high risk of
multiple cancers due to elevated genome instability, and its aberrant activity is known to influence therapeutic
response to cytotoxic chemotherapy that utilizes DNA cross-linking agents including platinum. Thus,
knowledge on molecular and genetic factors that control the FA pathway is expected to help us exploit their
deregulation for the development of improved cancer therapeutics. One of the fundamental regulatory
mechanisms for protein degradation is reversible phosphorylation of protein targets, which marks a protein to
be destroyed by ubiquitin-proteasome system. We recently discovered the proteolytic signaling pathway of
FAAP20, a key component of the FA core ubiquitin E3 ligase complex necessary for the FA pathway
activation, and showed that deregulation of FAAP20 leads to a functional disruption of the FA core complex,
impairing the ability of cells to repair DNA ICL lesions. Specifically, we defined SCFFBW7 as an ubiquitin E3
ligase complex responsible for phosphorylation-dependent FAAP20 degradation and demonstrated how its
deregulation affects the FA pathway. Our preliminary studies also indicate that phosphorylation-dependent
conformational change of FAAP20 regulated by cis-trans isomerase PIN1 modulates ubiquitin signaling of
FAAP20 degradation, thereby determining the fate of the FA core complex and influencing the efficiency of
DNA ICL repair. Herein, we propose to explicate PIN1-SCFFBW7 proteolytic signaling in controlling the FA
pathway and its impact to genome instability. Specifically, we will (1) dissect the signaling pathway of FAAP20
degradation regulated by SCFFBW7, (2) elucidate the mechanisms by which PIN1-driven structural change of
FAAP20 functions as a regulatory switch to control FAAP20 stability, and (3) determine the role of PIN1 in
regulating DNA ICL repair and the therapeutic response of breast cancer to platinum via FA pathway signaling
using cancer cell lines and a mouse model. Together, our studies are expected to reveal the first direct link
between a highly deregulated PIN1-SCFFBW7 axis in human cancer and DNA ICL repair. This work will
ultimately benefit human health by offering a unique opportunity to design therapeutic interventions that exploit
aberrant ...

## Key facts

- **NIH application ID:** 10358489
- **Project number:** 5R01CA218132-05
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Hyungjin Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,897
- **Award type:** 5
- **Project period:** 2018-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358489

## Citation

> US National Institutes of Health, RePORTER application 10358489, Proteolytic control of DNA interstrand cross-link repair and genome integrity (5R01CA218132-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10358489. Licensed CC0.

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