fig1

Figure 1. Mechanistic Overview of Programmed Meiotic Double-Strand Breaks (DSBs) Formation, Repair, and Crossover Pathway Choice. Programmed meiotic DSBs are initiated at PRDM9-defined recombination hotspots through recruitment of the SPO11-TOP6BL complex by the pre-DSB recombinosome. Following DSB formation, SPO11-bound DNA ends are processed by the MRE11-RAD50-NBS1 (MRN) complex together with CtIP, generating 3’ single-stranded DNA (ssDNA) overhangs. The exposed ssDNA is initially bound by replication protein A (RPA), while the MEIOB-SPATA22 complex contributes to the stabilization and processing of recombination intermediates. RAD51 and DMC1 are subsequently loaded onto ssDNA and promote homology search and strand invasion into the homologous chromosome. Recombination intermediates may be repaired by synthesis-dependent strand annealing (SDSA), resulting in non-crossover products, or proceed through crossover pathways. Class I crossovers are promoted by ZMM-associated factors, including MSH4-MSH5, HFM1, RNF212, HEI10, and the SHOC1-TEX11-SPO16 complex, which stabilize recombination intermediates and facilitate their maturation into double Holliday junction (dHJ) structures. These intermediates are subsequently resolved primarily by the MutLγ complex composed of MLH1 and MLH3 to generate interference-sensitive class I crossover products. Class II crossovers arise through an alternative, interference-independent pathway involving MUS81-EME1, whereas GEN1 may also contribute to the resolution of meiotic recombination intermediates. The blue and red lines represent chromatids from homologous chromosomes, whereas colored symbols represent key meiotic proteins or protein complexes involved in each step. Solid arrows indicate the major progression of meiotic recombination, and dashed arrows indicate intermediate processing steps. The pathways shown are based largely on studies of mammalian meiosis, particularly in mouse models; direct experimental evidence in humans remains limited for some steps. ZMM: Zip–Mer–Msh proteins; ZZS: Zip2–Zip4–Spo16 complex; CtIP: CtBP-interacting protein. Created in BioRender. yi, S. (2026) https://BioRender.com/48i53yr