# APOBEC proteins as drivers of chromosomal translocations in solid cancers

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $404,888

## Abstract

Summary
 Chromosomal translocations are key drivers of oncogenic transformation and frequently determine the
biology and response to therapy of cancer cells. The mechanisms that generate the DNA double strand breaks
(DSBs) that initiate chromosomal translocations are well known in hematologic cancers but poorly understood
in solid tumors. In lymphoma and leukemia, most DSBs that lead to an oncogenic translocation are generated
by the activity of enzymes such as RAG1/2 and AID. These enzymes are physiologically responsible for the
rearrangements of the immunoglobulin genes, but can initiate a translocation when they aberrantly target other
genes. In contrast, in solid tumors where RAG1/2 and AID are largely not expressed, it is unclear what factors
initiate DSB formation. Physical factors, such as UV light or irradiation, or factors intrinsic to the DNA structure
or replication are thought to be responsible for part of the DSB and translocation formation, but they are
insufficient to explain the recurrent patterns of oncogenic translocations in solid tumors. Recently, the APOBEC
proteins have been linked to peculiar mutational signatures found in several solid cancers, including lung and
breast cancers. Importantly, the APOBEC-dependent mutational signatures typically co-localize with genomic
rearrangements such as translocations and somatic copy number alterations (SCNAs). Based on these
correlative findings and preliminary experiments, our hypothesis is that APOBEC enzymes could be
responsible not only for somatic mutations but also for the formation of chromosomal translocation in solid
tumors. We will test this hypothesis by applying innovative sequencing techniques we developed in our lab to
identify and map recurrent translocations induced by APOBEC proteins in different cell types. We will apply
these techniques both in in vitro assays as well as to in vivo models of translocation formation. The
demonstration that APOBEC protein can initiate translocation formation has the potential to provide a key
mechanistic link that is currently missing to explain recurrent structural aberrations in cancer. From this
demonstration, a variety of new research lines will open including potential therapeutic applications aimed at
blocking APOBEC activity to reduce genomic instability in cancer.

## Key facts

- **NIH application ID:** 9828767
- **Project number:** 5R01CA222598-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Roberto Chiarle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,888
- **Award type:** 5
- **Project period:** 2017-12-18 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828767

## Citation

> US National Institutes of Health, RePORTER application 9828767, APOBEC proteins as drivers of chromosomal translocations in solid cancers (5R01CA222598-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9828767. Licensed CC0.

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