Abstract
Chromatin structure and function are for a large part determined by the six members of the structural maintenance of chromosomes (SMC) protein family, which form three heterodimeric complexes: Smc1/3 (cohesin), Smc2/4 (condensin) and Smc5/6. Each complex has distinct and important roles in chromatin dynamics, gene expression and differentiation. In yeast and Drosophila, Smc6 is involved in recombinational repair, restarting collapsed replication forks and prevention of recombination in repetitive sequences such as rDNA and pericentromeric heterochromatin. Although such DNA damage control mechanisms, as well as highly dynamic changes in chromatin composition and function, are essential for gametogenesis, knowledge on Smc6 function in mammalian systems is limited. We therefore have investigated the role of Smc6 during mammalian spermatogonial differentiation, meiosis and subsequent spermiogenesis. We found that, during mouse spermatogenesis, Smc6 functions as part of meiotic pericentromeric heterochromatin domains that are initiated when differentiating spermatogonia become irreversibly committed toward meiosis. To our knowledge, we are the first to provide insight into how commitment toward meiosis alters chromatin structure and dynamics, thereby setting apart differentiating spermatogonia from the undifferentiated spermatogonia, including the spermatogonial stem cells. Interestingly, Smc6 is not essential for spermatogonial mitosis, whereas Smc6-negative meiotic cells appear unable to finish their first meiotic division. Importantly, during meiosis, we find that DNA repair or recombination sites, marked by γH2AX or Rad51 respectively, do not co-localize with the pericentromeric heterochromatin domains where Smc6 is located. Considering the repetitive nature of these domains and that Smc6 has been previously shown to prevent recombination in repetitive sequences, we hypothesize that Smc6 has a role in the prevention of aberrant recombination events between pericentromeric regions during the first meiotic prophase that would otherwise cause chromosomal aberrations leading to apoptosis, meiotic arrest or aneuploidies.
Highlights
It has been shown that the yeast Smc5/6 complex is required to resolve meiotic recombination intermediates and that abrogation of the complex leads to unresolved linkages between the meiotic chromosomes.[15,16,17]
We found that when spermatogonia present in one section express Smc[6], the same cells in a neighboring section are negative for LIN28 (Figure 2b)
These spermatogonia are irreversibly committed to eventually enter meiosis and further divisions and development of these cells are strictly orchestrated by the stages of the seminiferous epithelium.[41,48]
Summary
The Smc5/6 complex was first described in yeast cells to be involved in the DNA damage response process by promoting sister chromatid recombination and recruiting cohesin to double-strand break (DSB) sites.[4,12,13,14] it has been shown that the yeast Smc5/6 complex is required to resolve meiotic recombination intermediates and that abrogation of the complex leads to unresolved linkages between the meiotic chromosomes.[15,16,17] DNA damage repair has long. In heterochromatic regions containing densely packed, highly repetitive DNA sequences such as rDNA and the pericentromeric regions, Smc5/6 maintains genomic stability by suppressing aberrant intra-chromosomal recombination between these repetitive sequences.[14,26,33,34] Smc[6] is required for repair of DSBs that occur in these heterochromatic regions[14,26,33] by having an essential role in the translocation of the damaged DNA to adjacent euchromatic regions where recombinational repair can be completed, safe from the complications associated with a high density of surrounding repetitive sequences.[34]. Failure to maintain genomic integrity can cause spermatogonial apoptosis, while later chromosomal misalignments can lead to infertility caused by meiotic arrest.[42] Even though proper chromatin architecture sits at the fundament of efficient and safe reproduction, surprisingly little is known about the changing chromatin dynamics that are already clearly visible during spermatogonial differentiation.[43,44]
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