Homologous Pairing Preceding SPO11-Mediated Double-Strand Breaks in Mice

Abstract

SUMMARY How homologous chromosomes (homologs) find their partner, pair and recombine during meiosis constitutes the central phenomenon in eukaryotic genetics. It is widely believed that in most organisms SPO11-mediated DNA double-strand breaks (DSBs) introduced during prophase I precede and are required for efficient homolog pairing. We now show that in the mouse, a significant level of homolog pairing precedes programmed DNA cleavage. Strikingly, this early chromosome pairing still requires SPO11, but is neither dependent on its ability to make DSBs nor homologous recombination proteins. Intriguingly, SUN1, a protein required for telomere attachment to the nuclear envelope and for post-DSB synapsis, is also required for early pre-DSB homolog pairing. Furthermore, pre-DSB pairing at telomeres persists upon entry into prophase I, and is most likely important for initiation of synapsis. Our findings suggest that the DSB-triggered homology search may mainly serve to proofread and stabilize the pre-DSB pairing of homologous chromosomes.

Meiosis-specific cohesin mediates homolog recognition in mouse spermatocytes

“…2A). These results are consistent with the previous observations (Scherthan et al 1996) but partly contradictory to a recent study that reports the appearance of a transient pairing peak at late premeiotic S phase (see the Discussion; Boateng et al 2013). Under our experimental conditions, the distance between paired FISH signals decreases to <1.35 mm in 45%;60% of zygotene spermatocytes and in >95% of pachytene spermatocytes (Fig.…”

“…2A). This result is contradictory to the previous observation that homolog pairing is abolished in Sun1 knockout spermatocytes (see the Discussion; Boateng et al 2013). Furthermore, FISH chromosome painting assays indicate that the initial chromosome association at the early leptotene stage is delayed in Sun1 knockout spermatocytes (Fig.…”

“…DSB-dependent recombination and subsequent synapsis, DSB-independent mechanisms seem to promote the juxtaposition of homologs (Weiner and Kleckner 1994;Peoples et al 2002;Storlazzi et al 2003;Bhuiyan and Schmekel 2004;Ding et al 2004;Peoples-Holst and Burgess 2005). A recent study in mice reported that a DSB-independent mechanism promotes homolog pairing during premeiotic S phase prior to DSB formation (Boateng et al 2013). The molecular mechanism of DSB-independent homolog recognition remains a mystery, although the aggregation of heterochromatin, noncoding RNA, the SPO11 protein, or sequence-specific DNA-binding proteins such as transcription factors are suggested to contribute to this process (Page and Hawley 2004;Barzel and Kupiec 2008;Dombecki et al 2011;Ding et al 2012;Boateng et al 2013).…”

“…A recent study in mice reported that a DSB-independent mechanism promotes homolog pairing during premeiotic S phase prior to DSB formation (Boateng et al 2013). The molecular mechanism of DSB-independent homolog recognition remains a mystery, although the aggregation of heterochromatin, noncoding RNA, the SPO11 protein, or sequence-specific DNA-binding proteins such as transcription factors are suggested to contribute to this process (Page and Hawley 2004;Barzel and Kupiec 2008;Dombecki et al 2011;Ding et al 2012;Boateng et al 2013).…”

The DNA Damage Response in Mammalian Oocytes.

“…However, recent findings have shown that homolog pairing is completely abolished in Spo11 −/− spermatocytes suggesting that Spo11 is also required for the DSBindependent initiation of synapsis (Boateng et al, 2013). Absence of the Spo11-dependent homolog pairing and DSB formation leads to oocyte apoptosis during early follicular development, soon after birth (Baudat et al, 2000;Di et al, 2005).…”