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. 2024 Dec;19(1):2381849.
doi: 10.1080/15592294.2024.2381849. Epub 2024 Aug 7.

GGNBP2 regulates histone ubiquitination and methylation in spermatogenesis

Kaimin Guo  1 , Yin Cao  1 , Zhiyi Zhao  1 , Jiantao Zhao  1 , Lingyun Liu  1 , Hongliang Wang  1
Affiliations

GGNBP2 regulates histone ubiquitination and methylation in spermatogenesis

Kaimin Guo et al. Epigenetics. 2024 Dec.

Abstract

Gametogenetin binding protein 2 (GGNBP2) was indispensable in normal spermatids for transformation into mature spermatozoa in mice, and when Gametogenetin binding protein 2 is bound to BRCC36 and RAD51, the complex participates in repairing DNA double-strand breaks (DSB) during the meiotic progression of spermatocytes. Ggnbp2 knockout resulted in the up-regulation of H2AK119ubi and down-regulation of H2BK120ubi in GC-2 cells (mouse spermatogonia-derived cell line) and postnatal day 18 testis lysate. Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change. Furthermore, the Gametogenetin binding protein 2 deletion reduced H2B ubiquitination by affecting E2 enzymes and E3 ligase binding. Gametogenetin binding protein 2 regulated H2A and H2B ubiquitination levels and controlled H3K27 and H3K79 methylation by PRC2 subunits and histone H3K79 methyltransferase. Altogether, our results suggest that Ggnbp2 knockout increased DNA damage response by promoting H2A ubiquitination and H3K27trimethylation (H3K27me3) and reduced nucleosome stability by decreasing H2B ubiquitination and H3K79 dimethylation (H3K79me2), revealing new mechanisms of epigenetic phenomenon during spermatogenesis. Gametogenetin binding protein 2 seems critical in regulating histone modification and chromatin structure in spermatogenesis.

Keywords: DNA repair; GGNBP2; H2A ubiquitination; H2B ubiquitination; histone modification; spermatogenesis.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Ggnbp2 controls both chromatin compaction and nucleosome stability.
Figure 2.
Figure 2.
Ggnbp2 deletion leads to the up-regulation of H2AK119ubi and the down-regulation of H2BK120ubi.
Figure 3.
Figure 3.
GGNBP2 interacts and colocalizes with ASXL1. The absence of GGNBP2 affects ASXL1 and BAP1 interaction as well as BAP1 translocation.
Figure 4.
Figure 4.
GGNBP2 interacts and colocalizes with UBE2B, and GGNBP2 loss affects UBE2B and RNF40 interaction.
Figure 5.
Figure 5.
GGNBP2 regulates histone H2A and H2B ubiquitination levels in vitro.
Figure 6.
Figure 6.
GGNBP2 controlled patterns of histone modification.
Figure 7.
Figure 7.
The mechanism of histone modifications regulated by GGNBP2.
See this image and copyright information in PMC

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