# Sex differences in DNA damage response

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $185,101

## Abstract

Abstract:
The sex of an individual has been associated with the frequency of various health conditions, responses
to disease treatment, incidence of drug-associated toxicities, and lifespan. The current literature
remains unclear and conflicting with regard to sex-dependent differences in DNA damage response,
especially as it relates to DNA damaging agents, such as radiation therapy (RT) which is an indicated
treatment in more than half of newly diagnosed cancers. Thus, pharmacodynamic (PD) biomarkers
based on assessment of DNA damage endpoints may prove valuable not only in translational and
clinical cancer research but in standard RT practices. Presently, there is a lack of robust validated PD
biomarkers that can quantify cellular responses to DNA damage. Ataxia telangiectasia mutated kinase
(ATM) is activated by DNA double-strand breaks (DSBs) through intermolecular autophosphorylation
on serine-1981. ATM serine-1981 phosphorylation (p-ATM) is increased >50% in cells exposed to as
little as 5 cGy γ-rays. This sensitivity/stoichiometry suggest that p-ATM may be an appropriate and
reliable PD biomarker of radiation-induced DNA damage. Thus, we developed a fit-for-purpose
quantitative multiplexed assay to analyze p-ATM and pan ATM protein. This assay documented the
first reported induction of p-ATM in patient PBMCs following radiation therapy or chemotherapy. To
address sex differences in ATM activation, we obtained PBMCs from male and female volunteers and
measured the normal basal levels of ATM as well as the ATM activation following ex vivo irradiation.
PBMCs isolated from women have a 2.6-fold greater induction of p-S1981-ATM expression than men
following exposure to 2 Gy IR. It is therefore likely that RT-induced p-ATM will differ between male and
female patients and that this difference may manifest as different responses and/or toxicities in the
clinical setting. We hypothesize that ATM phosphorylation at serine-1981 is a sensitive PD biomarker
of DNA damage response capable of defining sex differences and RT toxicities. To address this
hypothesis, we propose two specific aims in this application. Aim 1 will quantify DNA damage signaling
and repair in PBMCs from male and female cancer patients receiving RT. Aim 2 will evaluate and
quantify DNA damage signaling in sorted PBMCs obtained from normal subjects following ex vivo DNA
damage to identify specific immune cell populations most induced by radiation. Completion of these
Aims will validate p-ATM as a biomarker of DNA damage and repair in patients receiving RT and
advance p-ATM as a biomarker of radiation toxicity that may allow dose reduction such that patients
experiencing toxicity can complete their therapy.

## Key facts

- **NIH application ID:** 10435628
- **Project number:** 1R21CA263394-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JOHN C SCHMITZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $185,101
- **Award type:** 1
- **Project period:** 2022-04-18 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435628

## Citation

> US National Institutes of Health, RePORTER application 10435628, Sex differences in DNA damage response (1R21CA263394-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435628. Licensed CC0.

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