# Germline mutagenesis at meiotic double-strand breaks

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $444,686

## Abstract

Project Summary/Abstract
Meiotic recombination is essential for the reductional cell division in mammalian germ cells and thus for the
development of haploid gametes, i.e., sperm and eggs. Recombination is initiated by hundreds of DNA double-
strand breaks (DSBs) introduced genome-wide that are catalyzed by the SPO11 protein. Faithful transmission
of the genome to subsequent generations requires proper repair of these numerous DSBs, primarily through
recombination with the homolog. DSB formation is regulated in meiotic cells by the ATM kinase, which is
known to be a primary responder to DSBs in mitotic cells, such that in the absence of ATM, meiotic DSBs
increase ~10-fold.
 We recently discovered that meiotic DSBs are at risk for provoking germline rearrangements, in
particular deletions and tandem duplications involving nonhomologous end-joining, especially in the absence of
ATM. These events are consequential in terms of disrupting the genes in which these hotspots occur as well
as the associated PRDM9 binding sites that govern recombination at those loci. Thus, our findings reveal a
previously hidden potential for germline mutagenesis that is likely to affect human health and genome
evolution. In humans, recent long-range sequencing of Icelanders supports this impact. This proposal pursues
aims to understand the mechanisms that give rise to these events, the range of events at meiotic DSBs, and
the effect of age. We hypothesize that other rearrangements are possible at meiotic DSBs than what we have
previously identified. Thus, in the first aim, we propose to determine the range of mutagenic outcomes that can
arise from meiotic DSBs, including long-range deletions and duplications and chromosomal translocations. In
the second aim, we examine factors that may impact the formation of deletions. We focus on the effect of DNA
end processing at two steps, SPO11 removal and end processing, and recombination. Further, we address
whether gaps formed at nearby DSBs are substrates for homologous recombination and the impact of paternal
age in the rearrangement events at meiotic DSBs.

## Key facts

- **NIH application ID:** 10901908
- **Project number:** 5R01HD112624-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Maria Jasin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,686
- **Award type:** 5
- **Project period:** 2023-08-08 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901908

## Citation

> US National Institutes of Health, RePORTER application 10901908, Germline mutagenesis at meiotic double-strand breaks (5R01HD112624-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901908. Licensed CC0.

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