# Mechanism of Disease-causing mutations in PCNA

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $383,722

## Abstract

Abstract
PCNA is a critical regulator and facilitator of many cellular processes such as
DNA replication, DNA repair, recombination, chromatin structure and apoptosis.
PCNA is a ring-shaped complex that acts as a sliding platform on DNA for the
arrangement of scores different proteins to assemble and act on chromatin.
Abnormal PCNA activity is associated with the development and metastasis of
cancer; consequently, PCNA is a target for development of chemotherapeutics.
Two separate point mutations (Ser228Ile and Cys148Ser) in PCNA cause an
autosomal recessive disorder (PCNA Associated DNA Repair Disorder or PARD)
that results from defects in DNA repair. We hypothesize that these mutations
disrupt PCNA’s stability and/or ability to bind to partner proteins. We further
hypothesize that the PCNA defect in folding stability results in a shorter lifetime
on DNA, thereby preferentially inhibiting DNA repair proteins that function near
the end of PCNA’s lifetime on DNA. Our preliminary studies show that the S228I
mutation disrupts the binding site for PCNA partners, yet some partners
overcome this disruption to bind PCNA. We hypothesize that the S228I mutation
disrupts the structure and dynamics of the binding site such that the DNA repair
pathway is disproportionately perturbed. We further find that both PARD
mutations disrupt PCNA stability, which could decrease the lifetime of PCNA on
DNA. In support of this hypothesis, we find that PCNA levels on chromatin are
abnormally low in patient-derived fibroblast cells.
We will address these hypotheses with three specific aims: (1) To determine how
the PARD mutations alter PCNA structure, stability, and dynamics, (2) to
determine the biochemical effects of PARD variants on PCNA longevity and on
partner binding and activity, and (3) to identify which cellular factors and
pathways are disrupted. Our studies will determine the robustness or fragility of
PCNA-mediated pathways such as DNA repair and DNA replication, which will
define how PCNA affects cancer. Our work will also uncover how PCNA structure
and dynamics controls partner binding, which will guide efforts to develop small
molecules that disrupt specific PCNA-mediated.

## Key facts

- **NIH application ID:** 10422875
- **Project number:** 1R01GM145943-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Brian Anthony Kelch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,722
- **Award type:** 1
- **Project period:** 2022-09-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10422875

## Citation

> US National Institutes of Health, RePORTER application 10422875, Mechanism of Disease-causing mutations in PCNA (1R01GM145943-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10422875. Licensed CC0.

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