# Impacts of APOBECs on DNA replication, ATR checkpoint, and cancer therapy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $379,176

## Abstract

Project Summary
Genomic instability is a hallmark of cancer. The genomic instability in cancer cells arises from multiple sources,
such as defects in cell-cycle control, DNA replication, and DNA repair. Recent cancer genomics studies have
revealed that the mutation signatures in different cancers are distinct, reflecting the different types of oncogenic
stress that cancer cells have experienced during the process of tumorigenesis. In particular, the mutation
signatures associated with APOBEC3A/B cytosine deaminases are prevalent in several cancer types,
suggesting that these APOBEC proteins are important drivers of mutation in a subset of cancers. Interestingly,
recent studies have suggested that APOBEC3A/B proteins may act during DNA replication on the lagging strand
of replication forks, raising a question as to whether APOBECs induce replication stress in cancer cells. In our
preliminary studies, we have found evidence that APOBEC3A/B, through their cytosine deaminase activity,
induce a unique type of replication stress in cancer cells and activate the ATR-mediated replication stress
response. Furthermore, we found that cancer cells harboring high APOBEC activity are increasingly sensitive to
ATR inhibition. These findings have led us to hypothesize that APOBECs impose a unique type of “mutator-
driven” replication stress in cancer cells, which renders the cancer cells harboring high APOBEC activity
susceptible to ATR inhibition. In our proposed studies, we will systematically investigate how APOBECs induce
replication stress, how ATR suppresses the APOBEC-induced genomic instability, and how we can specifically
target the unique APOBEC stress in cancer cells. The completion of these studies may provide a new view of
the replication stress in cancer cells, and bring about a novel therapeutic strategy that may significantly improve
the treatment of several cancer types.

## Key facts

- **NIH application ID:** 10152561
- **Project number:** 5R01CA218856-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Lee Zou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $379,176
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152561

## Citation

> US National Institutes of Health, RePORTER application 10152561, Impacts of APOBECs on DNA replication, ATR checkpoint, and cancer therapy (5R01CA218856-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10152561. Licensed CC0.

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