Figure 6. Preleptotene DSB-independent pairing in mice.

Our data argues for a progressive increase in telomeric homolog pairing which serves to promote interstitial pairing at multiple loci along the whole chromosome, prior to DSB formation occurring at the onset of meiotic prophase I (leptotene). Preleptotene pairing is DSB-independent but requires the topoisomerase II-like protein SPO11, and the protein anchoring telomeres to the nuclear envelope (NE), SUN1. We propose that the tethering of telomeres to the nuclear envelope in late preleptotene (Chehrehasa et al., 2009; Scherthan et al., 1996) (Figures 4 and S4), facilitates the initiation of homolog pairing at subtelomeric regions by simplifying the search for the cognate partner. Upon entry into prophase, DSB-independent pairing at interstitial (non-telomeric) sites is lost, presumably to allow for the removal of unwanted associations and entanglements. However, telomeric pairing is maintained at least at one end, as long as the homologous recombination (HR) machinery is functional. While interstitial interactions are lost, we cannot rule out the possibility that the homologs stay in close proximity. Also, this reversibility in interstitial pairing may permit or promote strand invasion mediated by the HR machinery. Thus the HR may only serve to proofread the initial pairing established prior to DSB formation and as a checkpoint to ensure that ectopic associations are disrupted. Subsequently, “validated” interactions would be stabilized via the polymerization of the synaptonemal complex (synapsis). Furthermore, DSB repair and synapsis, initiating at the preserved preleptotene homologously paired telomeric sites, extends into the chromosome to restore pairing at interstitial sites, ultimately leading to a progressive synapsis (almost zipper-like) of homologs later in prophase I.