# Mapping DNA Repair and Error-Prone DNA Synthesis in Geriatric Skin

> **NIH VA I01** · DAYTON VA MEDICAL CENTER · 2021 · —

## Abstract

PROJECT SUMMARY/ABSTRACT
 Non-melanoma skin cancers (NMSCs) are a growing problem among our nation’s Veteran population,
and current treatments are both costly and potentially disfiguring. The primary risk factors for NMSC development
are exposure to ultraviolet B (UVB) wavelengths of sunlight and advanced age. Though the mutagenic effects of
UVB-induced bipyrimidine dimers in genomic DNA are well known, the mechanisms by which age impacts UVB-
dependent NMSC initiation in skin keratinocytes are less clear. The unique structural and physiological properties
of geriatric skin likely influence both the number and distribution of photolesions that form across the genome of
basal keratinocytes after UV exposure and the ways in which these cells respond to the damage. Moreover,
aged tissues including skin are known to contain a higher number of senescent dermal fibroblasts than younger
skin, which may alter cytokine and growth factor production and contribute to a pro-tumorigenic
microenvironment. One such factor that is expressed at lower levels in geriatric skin is insulin-like growth factor
1 (IGF-1). Our published and preliminary data show that the loss of IGF-1/IGF-1 receptor (IGF-1R) signaling in
epidermal keratinocytes results in UVB-irradiated keratinocytes that are unable to efficiently remove UVB
photoproducts from DNA or to properly activate the apical DNA damage response kinase ATR, which functions
to suppress error-prone DNA synthesis on damaged DNA templates. The objective of this proposal is to
determine how age and specifically IGF-1 receptor activation affect the formation and replication of UVB DNA
photoproducts in basal epidermal keratinocytes in human skin. The background of the research team, which
includes expertise in DNA repair, replication stress response signaling, genomics, keratinocyte biology, and
clinical dermatology, makes this group uniquely qualified to address this important clinical issue. The central
hypothesis of this proposal is that the skin of geriatric individuals is prone to carry out a more mutagenic form of
DNA synthesis following UVB exposure than the skin of younger individuals. This hypothesis has been derived
from significant preliminary and published data with both cultured keratinocytes in vitro and human skin biopsies
ex vivo and in vivo. The rationale for this proposed research is that it will define how the unique features of
geriatric skin predispose it to UVB mutagenesis and carcinogenesis. Our hypothesis will be tested by carrying
out the following three specific aims: Aim 1) Define how age and IGF-1 status influence UVB-induced DNA
photoproduct formation and repair across the keratinocyte genome in human skin epidermis; Aim 2) Determine
how IGF-1 signaling impacts the utilization of error-prone DNA polymerases in UVB-irradiated human skin
explants ex vivo and cultured keratinocytes in vitro; and Aim 3) Define how subject age and IGF-1 status affect
the replication of UVB-damaged DNA in human ski...

## Key facts

- **NIH application ID:** 10253181
- **Project number:** 1I01CX002241-01A1
- **Recipient organization:** DAYTON VA MEDICAL CENTER
- **Principal Investigator:** Michael George Kemp
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253181

## Citation

> US National Institutes of Health, RePORTER application 10253181, Mapping DNA Repair and Error-Prone DNA Synthesis in Geriatric Skin (1I01CX002241-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10253181. Licensed CC0.

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