DCAF2 regulates the proliferation and differentiation of mouse progenitor spermatogonia by targeting p21 and thymine DNA glycosylase

DDB1-cullin-4-associated factor-2 (DCAF2, also known as DTL or CDT2), a conserved substrate recognition protein of Cullin-RING E3 ligase 4 (CRL4), recognises and degrades several substrate proteins during the S phase to maintain cell cycle progression and genome stability. Our study found that Dcaf2 was highly expressed in the germ cells of human and mouse testes. To determine whether DCAF2 plays a crucial role in spermatogenesis, we generated germ cell conditional Dcaf2 knockout mice by crossing Dcaf2fl/fl mice with Stra8-Cre mice. The depletion of Dcaf2 in germ cells causes a reduction in progenitor spermatogonia and differentiating spermatogonia, eventually leading to the failure of meiosis initiation and male infertility. Further study showed that depletion of Dcaf2 in germ cells caused abnormal accumulation of the substrate proteins cyclin-dependent kinase inhibitor 1A (p21) and thymine DNA glycosylase (TDG). Overexpression of p21 or TDG attenuates proliferation and increases DNA damage and apoptosis in GC-1 cells. Co-overexpression of p21 and TDG exacerbates DNA damage and apoptosis. These results suggest that DCAF2 maintains the expansion and differentiation of progenitor spermatogonia by targeting the substrate proteins p21 and TDG.