HELQ Maintains Genome Stability of Primordial Germ Cells by Inhibiting LINE-1 Expression

Abstract

The DNA helicase HELQ is involved in homologous recombination repair, interstrand cross-link repair, and replication stress response. Its functional defects are associated with infertility and abnormal gametogenesis. However, the specific mechanisms of HELQ in the development of germ cells remain to be elucidated. Here, we uncovered that HELQ deficiency led to proliferation defects of primordial germ cells (PGCs) in mouse embryos, thus compromising the establishment of reproductive reserve. Mechanistically, we found that HELQ interacted with the H3K9me3 demethylase KDM4B, and the absence of HELQ led to a marked increase in both total and chromatin-bound protein levels of KDM4B, resulting in reduced H3K9me3 levels in the region of the retrotransposon LINE-1, which triggered its high expression and subsequently caused DNA damage accumulation. Moreover, the developmental defects of HELQ-deficient PGCs were alleviated by inhibition of retrotransposition. These results indicate that HELQ maintains the genome stability of PGCs by repressing LINE-1 expression. Our study reveals a critical role of HELQ in PGC development and provides new insights into reproductive disorders caused by defects in DNA damage response factors.

Keywords: DNA damage response; HELQ; LINE‐1; primordial germ cells; retrotransposition.