# A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $360,281

## Abstract

Abstract
A crucial first step in DNA repair involves the recognition of genome damage, which in turn activates
signaling pathways that recruit effectors and resolve the lesion. However, whether this “sensor-
transducer-mediator” paradigm is generally applicable to pathways dedicated to repairing each
distinct type of DNA lesion remains unknown. Understanding the signaling events that mediate the
recognition and repair of DNA alkylation damage is particularly important, since alkylation
chemotherapy is one of the most widely used systemic modalities for cancer treatment. Our
preliminary studies demonstrate that human cells have a heretofore unrecognized repair signaling
pathway that is highly specific for recruiting alkylation repair factors to nuclear foci and link this
pathway to an inherited human disease. Since multiple alkylation repair factors appear to be recruited
to these foci, we have termed them nuclear SCARs (Specialized Centers for Alkylation Repair). In this
proposal, we seek to understand whether recruitment of alkylation repair factors to these sites is
critical for resolution of alkylation repair (Aim 1). We will characterize the upstream E3 ubiquitin ligase,
RNF113A, which we have found to play a central role in this pathway and is mutated in the progeroid
syndrome trichothiodystrphy (Aim 2). Finally, we will test whether targeting this pathway could
promote chemosensitization in human tumor models (Aim 3). These studies will greatly increase our
understanding of how cells detect and activate DNA repair pathways. Since alkylation repair is critical
for reversing the toxic effects of many chemotherapy agents, our work will provide new insights into
how cell respond to such therapy, and may reveal several novel molecular targets for
chemosensitization.

## Key facts

- **NIH application ID:** 10192678
- **Project number:** 5R01CA227001-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Nima Mosammaparast
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,281
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192678

## Citation

> US National Institutes of Health, RePORTER application 10192678, A SIGNALING PATHWAY SPECIFIC FOR ALKYLATION DAMAGE (5R01CA227001-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10192678. Licensed CC0.

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