# Role of DNA Damage Responses in Immune Development and Function

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2020 · $315,000

## Abstract

PROJECT SUMMARY
Lymphocyte development is precisely controlled to enable clonal expansion and generation of a diverse
immunoglobulin receptor repertoire, which proceeds through DNA double-stranded breaks (DSBs). These two
dichotomous, but interdependent processes, are managed through the cooperation of diverse cellular signals to
prevent cells with DSBs from entering cell cycle where they could be aberrantly repaired as translocations. During
early B cell development, the pre-B cell receptor (pre-BCR), through activation of the SYK kinase, coordinates
both the proliferative expansion of pre-B cells and the assembly of immunoglobulin receptor genes. Negative
regulation of the pre-BCR is required to enforce cell cycle arrest and limit the number of DNA breaks generated
during immunoglobulin receptor gene assembly. Indeed, unopposed pre-BCR signaling, particularly increased
SYK activity, drives proliferation and leukemic transformation. We have identified a novel cell-type specific
checkpoint pathway activated by signals from DSBs that inhibits pre-BCR signaling. The physiologic DSBs
generated during immunoglobulin receptor gene rearrangement trigger DNA damage responses that suppress
SYK kinase activity downstream of the pre-BCR. Surprisingly, this signaling network is not triggered by genotoxic
DNA injury and, thus, is specific to the DSBs generated during normal B cell differentiation. In early B cells,
distinct cellular responses to physiologic and genotoxic DSBs are essential for ensuring normal B cell
differentiation and inhibiting leukemic transformation. Our goal is to determine how signals from DSBs
integrate with developmental programs to coordinate B cell maturation. We propose that early B cells
toggle between signals from the pre-BCR and DSBs to order immunoglobulin receptor gene assembly and
maintain genomic stability by preventing proliferation of cells with DSBs. Utilizing an innovative experimental
approach that permits isolation of DSB signals and surface receptor signals, we propose to: 1) define the
transcriptional repressor complex that regulates DSB-mediated checkpoints, 2) identify the DSB-dependent
post-translational pathways that suppress pre-BCR signaling, and 3) determine the DSB-specific pathways that
dictate the unique cellular responses to physiologic versus genotoxic insults. Completion of these studies will
delineate a set of mechanisms critical for dampening pre-BCR signals, will establish novel paradigms for cell-
type specific checkpoints to DSBs, and will define the underlying principles for discrete cellular responses to
physiologic versus genotoxic DSBs.

## Key facts

- **NIH application ID:** 10197574
- **Project number:** 1R56AI153234-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jeffrey J Bednarski
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197574

## Citation

> US National Institutes of Health, RePORTER application 10197574, Role of DNA Damage Responses in Immune Development and Function (1R56AI153234-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197574. Licensed CC0.

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