# The mutational mechanisms shaping melanocytes in human skin

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $399,002

## Abstract

Project Summary/Abstract
As a barrier organ, skin forms the main defense against ultraviolet (UV) radiation, a potent mutagen emitted by
the sun. The mutational damage incurred through this role can lead to melanoma, the deadliest form of skin
cancer. Contrary to expectations, melanoma is more common on body sites that are only exposed to UV
radiation intermittently, such as the back and shoulder, rather than body sites exposed more continuously,
such as the head/neck areas. We recently reported the first catalogue of somatic mutations in melanocytes
from normal human skin and discovered that melanocytes from the back/trunk had higher mutation burdens
than donor-matched melanocytes from the head/neck areas. Based on our mutational observations and the
anatomic patterns of melanoma, we hypothesize that melanocytes on the head/neck areas have evolved
mechanisms to accumulate mutations more slowly than melanocytes from other body sites – likely an
adaptation to counterbalance the higher levels of cumulative sun exposure affecting those sites. If true, this
would alter prevention strategies. Moreover, a better understanding of the mechanisms by which melanocytes
accumulate mutations would reveal molecular strategies to slow down this process and reduce the incidence of
melanoma.
We will test our hypothesis in aim 1 by comparing somatic mutations in melanocytes of different anatomic
origins within-people and in aim 2 by cataloguing somatic mutations in site-matched melanocytes across
people who offer detailed histories of sun exposure. These studies will offer correlative data implicating the
main factors driving up the mutation burdens in melanocytes. A major obstacle to these studies is that it is
difficult to measure somatic mutations in individual cells at a high degree of accuracy. However, we recently
pioneered a workflow to call mutations in individual melanocytes at nearly 100% specificity and sensitivity. To
complement these observational studies, in aim 3, we will measure in vitro the rates at which melanocytes of
different anatomic origins repair DNA damage and dissect the main mechanisms regulating this process.
Towards this goal, we have developed assays to measure UV-radiation-induced DNA damage at single base-
pair resolution in tissue-cultured cells. Taken together, the scientific approaches employed in this proposal are
technologically innovative and will illuminate the mutational mechanisms operating on melanocytes in normal
human skin, addressing major gaps in knowledge that have vexed the skin research community.

## Key facts

- **NIH application ID:** 10789978
- **Project number:** 5R01AR080626-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alan Hunter Shain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,002
- **Award type:** 5
- **Project period:** 2023-02-17 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789978

## Citation

> US National Institutes of Health, RePORTER application 10789978, The mutational mechanisms shaping melanocytes in human skin (5R01AR080626-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10789978. Licensed CC0.

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