# MYSM1-dependent DNA damage responses in early B cell development

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $196,875

## Abstract

PROJECT SUMMARY
Inborn errors of immunity provide unique opportunities to investigate the role of identified genes in the
development and function of the immune system. Investigation of these immune disorders has provided
important insights into human immunity and has established fundamental principles of basic and clinical
immunology. In this regard, germline variants in MYSM1 have recently been identified in patients with primary
immune deficiency characterized by low T cells, near complete absence of B cells, hypogammaglobulinemia,
and increased sensitivity to genotoxic agents. The role of MYSM1 in immune development and in cellular
response to DNA damage remain a critical knowledge gap. Deficiency of MYSM1 results in increased DNA
damage signals, particularly in B cells, in the absence of exposure to DNA damaging agents. During early
development, B cells (and T cells) generate DNA breaks to assembly the genes that encode their antibody
receptors. These DNA breaks are essential for creating the diversity of the immune system to recognize various
pathogens. In preliminary experiments, we find that, in response to these programmed DNA breaks, loss of
MYSM1 results in persistent DNA damage signaling, including activation of cell death programs, which impairs
B cell maturation. Our goal is to determine the mechanism of MYSM1 in regulation of cellular responses
to DNA damage and in coordination of B cell development. We propose that MYSM1 functions to terminate
DNA damage responses after DNA break repair and that this activity is critical for suppressing cell death
pathways to promote continued B cell development. We will define the role of MYSM1 in DNA damage signaling
in early B cells and will determine the mechanisms that regulate MYSM1 activity. Understanding the signals that
direct DNA damage programs in immune cells is essential for elucidating mechanisms of primary immune
deficiency and for optimizing treatment approaches. These studies will establish a new paradigm for inactivating
DNA damage responses and will reveal new opportunities to improve clinical management of patients with
MYSM1 deficiency as well as patients with abnormalities in other DNA damage pathways.

## Key facts

- **NIH application ID:** 10527156
- **Project number:** 1R21AI166259-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jeffrey J Bednarski
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527156

## Citation

> US National Institutes of Health, RePORTER application 10527156, MYSM1-dependent DNA damage responses in early B cell development (1R21AI166259-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10527156. Licensed CC0.

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