# FA DDR Pathway in Germline Integrity

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $329,925

## Abstract

Abstract
Genome maintenance in the germline is vital for fertility and the health of offspring. Although DNA
damage response (DDR) and repair has been well characterized in meiocytes, the DDR
pathway(s) that function in primordial germ cells (PGCs), which are the precursors to sperm and
eggs, have not been identified. Fanconi anemia (FA) is a genomic instability syndrome associated
with PGC depletion and infertility in addition to some other devastating clinical manifestations
such as bone marrow failure and cancer predisposition. The FA pathway is a major DDR pathway
known to function in double-strand DNA break repair. The signaling mechanisms underlying PGC
depletion and infertility in FA patients or mouse models are not known. We recently developed
Flag- and hemagglutinin-tagged Fancd2 knock-in mice that allowed a high throughput mass
spectrometry approach to search for Fancd2-binding proteins in different mouse organs. In
addition to DDR partners, we observed several proteins of the germ-cell-specific Prmt5/piRNA
pathways orchestrating the repression of transposable elements (TEs). Deletion of Fancd2
resulted in decreased protein levels of the Prmt5/piRNA factors, massive upregulation of TEs,
PGC depletion, and led to defective spermatogenesis and oogenesis in Fancd2-null (Fancd2-KO)
mice. These preliminary studies suggest that in addition to its well-established DNA repair roles,
Fancd2 and the FA pathway has an in vivo TE silencing function in early-stage germ cells. We
hypothesize that the FA pathway is essential for germline integrity involving a pathway hierarchy
in which the FA core signals to Fancd2, which then guides Prmt5 and piRNA in TE silencing. The
goals of the project are to establish functional interaction between the FA pathway and germ cell-
specific TE silencing machinery in safeguarding the germline genome, and to define Fancd2 as
a crucial regulator of this vital epigenetic programming during germ cell development.
 The project presents an innovative study aimed at linking a major DDR pathway to germline
genome maintenance in early-stage germ cells. The knowledge gained from the proposed study
will not only improve mechanistic understanding of the molecular collaboration between the FA
DDR pathway and the Prmt5/piRNA pathway in the context of TE repression, but also lead to a
new avenue of research designed to target these interacting pathways for developing innovative
therapeutic strategies for reproductive diseases such as infertility and birth defects.

## Key facts

- **NIH application ID:** 9918948
- **Project number:** 5R01HD089932-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** QISHEN PANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,925
- **Award type:** 5
- **Project period:** 2017-08-11 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918948

## Citation

> US National Institutes of Health, RePORTER application 9918948, FA DDR Pathway in Germline Integrity (5R01HD089932-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9918948. Licensed CC0.

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