Abstract
Chromosome inheritance during sexual reproduction relies on deliberate induction of double-strand DNA breaks (DSBs) and repair of a subset of these breaks as interhomolog crossovers (COs). Here we provide a direct demonstration, based on our analysis of rad-50 mutants, that the meiotic program in Caenorhabditis elegans involves both acquisition and loss of a specialized mode of double-strand break repair (DSBR). In premeiotic germ cells, RAD-50 is not required to load strand-exchange protein RAD-51 at sites of spontaneous or ionizing radiation (IR)-induced DSBs. A specialized meiotic DSBR mode is engaged at the onset of meiotic prophase, coincident with assembly of meiotic chromosome axis structures. This meiotic DSBR mode is characterized both by dependence on RAD-50 for rapid accumulation of RAD-51 at DSB sites and by competence for converting DSBs into interhomolog COs. At the mid-pachytene to late pachytene transition, germ cells undergo an abrupt release from the meiotic DSBR mode, characterized by reversion to RAD-50-independent loading of RAD-51 and loss of competence to convert DSBs into interhomolog COs. This transition in DSBR mode is dependent on MAP kinase-triggered prophase progression and coincides temporally with a major remodeling of chromosome architecture. We propose that at least two developmentally programmed switches in DSBR mode, likely conferred by changes in chromosome architecture, operate in the C. elegans germ line to allow formation of meiotic crossovers without jeopardizing genomic integrity. Our data further suggest that meiotic cohesin component REC-8 may play a role in limiting the activity of SPO-11 in generating meiotic DSBs and that RAD-50 may function in counteracting this inhibition.
Highlights
Faithful inheritance of chromosomes during meiosis relies on crossover (CO) recombination events between the DNA molecules of homologous chromosomes
We show that C. elegans germ cells engage a specialized mode of double-strand break repair (DSBR) at the onset of meiotic prophase, characterized by dependence on RAD-50 for rapid accumulation of RAD-51 at doublestrand break (DSB) and by competence to convert DNA breaks into interhomolog crossovers
Our data further suggest a model in which features of chromosome structure conferred by the meiotic cohesin component REC-8 may limit the activity of SPO-11 in generating meiotic DSBs
Summary
Faithful inheritance of chromosomes during meiosis relies on crossover (CO) recombination events between the DNA molecules of homologous chromosomes. Interhomolog COs underpin the formation of chiasmata that temporarily link homologs and allow them to orient and segregate toward opposite poles of the meiosis I spindle [1]. This requirement for crossovers to ensure homolog segregation poses a challenge for sexually reproducing organisms, as meiotic recombination is initiated by formation of doublestrand DNA breaks (DSBs) [2], lesions that constitute a danger to genomic integrity in other contexts. The idea that germ cells might possess mechanisms to inactivate features of the meiotic recombination program that serve as impediments to DSB repair (DSBR) has not been widely articulated. We had previously proposed that distinct modes of DSBR might operate during different stages of meiotic prophase in C. elegans to ensure restoration of intact chromosomes [3,4], the prior evidence for this assertion was indirect and largely circumstantial
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