Mammalian BLM helicase is critical for integrating multiple pathways of meiotic recombination

Abstract

Improper chromosome pairing, synapsis, and segregation impair meiotic progression in the absence of the BLM helicase in mammalian cells.

Meiotic double strand breaks repair in sexually reproducing eukaryotes: We are not all equal

“…The phenotypic analysis revealed that spermatocytes display non-homologous synapse defects regardless from the fact that MSH4/5 and MLH3/MLH1 pathways are intact, thus indicating that BLM prevent non-homologous synapses via a mechanism that does not affect the major DSB repair pathway. In addition, contrary to what is observed in C. elegans, CKO spermatocytes, beside a normal number of MLH1 foci, present an increase in chiasmata or chiasmata-like structures, indicating that BLM is required to prevent or resolve aberrant CO events [62]. Interestingly, Mlh3−/− spermatocytes display an increased number of BLM foci.…”

“…Interestingly, Mlh3−/− spermatocytes display an increased number of BLM foci. This has suggested that in normal meiosis the access of BLM to CO intermediates is prevented (perhaps by the ZMM protein group) and as a consequence its anti-recombination activity would be directed against recombination intermediates to which MLH1-MLH3 do not bind [62].…”

DNA Helicase HIM-6/BLM Both Promotes MutSγ-Dependent Crossovers and Antagonizes MutSγ-Independent Interhomolog Associations During Caenorhabditis elegans Meiosis

“…For example, in S. cerevisiae and Drosophila, loss of BLM orthologs during meiosis suppressed the CO deficits in mutants lacking "anti-anti-CO" factors, i.e., MutSg in budding yeast and the mei-MCM complex in flies (Jessop et al 2006;Oh et al 2007;Kohl et al 2012). Further, loss of BLM function in mouse germ cells was associated with elevated numbers of chiasmata (Holloway et al 2010).…”

“…Supporting the view of BLM as an anti-CO agent, BLM was identified as part of a protein complex that has an in vitro "dissolution" activity that can dismantle model recombination substrates containing double Holliday junctions in a manner that exclusively yields noncrossover products (Wu and Hickson 2003). Further, anti-CO roles during meiotic recombination have been demonstrated or proposed for BLM orthologs or its protein complex partners in a variety of species, including Saccaromyces cerevisiae, Arabidopsis, mice, and Drosophila (e.g., Rockmill et al 2003;Jessop et al 2006;Oh et al 2007;Chelysheva et al 2008;Holloway et al 2010;Kohl et al 2012). However, this reputation of BLM as an antagonist of crossing over was not readily reconciled with the finding that loss of function of him-6 results in a reduction of COs and chiasmata, implying a pro-CO rather than anti-CO role for BLM in C. elegans meiosis (Zetka and Rose 1995;Wicky et al 2004).…”

Clamping down on mammalian meiosis

“…One possibility is that a DNA structure generated at these particular break sites requires 9-1-1 for recognition or processing during the course of repair. It might be that these are recombination events involving multiple chromatids, such as those seen in BLM/ Sgs1 helicase and Mus81 endonuclease mutants, [72][73][74] which would be consistent with the observation of persistent paired RAD51 foci on either side of the SC axial elements in diplotene-stage Hus1 CKO spermatocytes. 15 Such a model would fit well with the recently identified role of yeast 9-1-1 in error-free DNA damage tolerance, where it functions in homologous recombination and template switching in mitotic cells, resulting in the formation of sister chromatid joint molecules that require resolution by SGS1 helicase (homolog of mammalian BLM) and TOP3 topoisomerase (homolog of mammalian TOP3A).…”