# Project 1: Base Repair: Molecular response to base-modifying chemotherapeutic agents

> **NIH NIH P01** · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · 2021 · $248,356

## Abstract

SUMMARY - PROJECT 1: Molecular response to base-modifying chemotherapeutic agents
Repair of base damage on DNA is critical because such damage is both genotoxic and mutagenic. Many
chemotherapeutic agents used for cancer therapy, such as cisplatin and alkylating agents, induce this type of
damage and are one of the most commonly used modalities for treatment, underscoring their clinical significance.
While much is known about how cells respond to DNA containing base damage, the importance of RNA damage
has become increasingly appreciated only recently. Indeed, alkylated RNA is estimated to comprise the vast
majority of the damaged nucleic acid in cells treated with such agents. It is not surprising then that cells have
evolved a number of mechanisms to cope with damaged RNA. We have discovered that the ALKBH3-ASCC
repair complex mediates the cellular response to DNA as well RNA base damage. This complex also interfaces
with the innate immune or DAMP (damage-associated molecular pattern) signaling through a novel RNA
endonuclease activity, which we have recently uncovered through the multidisciplinary efforts of this program
project. Our work implicates RNA damage recognition and signaling as a critical node in the cellular response to
base damage, an underexplored area, which we seek to understand in this renewal application. Specifically, we
will use a combination of structural methods and biochemistry to reveal the mechanistic basis of the enzymatic
activities within the ALKBH3-ASCC complex (Aim 1). We will also determine the importance of ASCC-mediated,
RNA-dependent DAMP signaling in the response to commonly used chemotherapeutic agents and its role in cell
fate decisions (Aim 2). Finally, we will determine how the ALKBH3-ASCC pathway integrates with established
base repair pathways, potentially identifying novel additive or synthetic lethal relationships between these
pathways (Aim 3). Together, the proposed work will reveal important insights into the contribution of RNA as well
as DNA base damage responses and its relevance to tumor cell eradication.

## Key facts

- **NIH application ID:** 10271092
- **Project number:** 2P01CA092584-21
- **Recipient organization:** UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
- **Principal Investigator:** Susan Emiko Tsutakawa
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,356
- **Award type:** 2
- **Project period:** 2001-09-27 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271092

## Citation

> US National Institutes of Health, RePORTER application 10271092, Project 1: Base Repair: Molecular response to base-modifying chemotherapeutic agents (2P01CA092584-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10271092. Licensed CC0.

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