MRG-1 is required for genomic integrity in Caenorhabditis elegans germ cells

Abstract

During meiotic cell division, proper chromosome synapsis and accurate repair of DNA double strand breaks (DSBs) are required to maintain genomic integrity, loss of which leads to apoptosis or meiotic defects. The mechanisms underlying meiotic chromosome synapsis, DSB repair and apoptosis are not fully understood. Here, we report that the chromodomain-containing protein MRG-1 is an important factor for genomic integrity in meiosis in Caenorhabditis elegans. Loss of mrg-1 function resulted in a significant increase in germ cell apoptosis that was partially inhibited by mutations affecting DNA damage checkpoint genes. Consistently, mrg-1 mutant germ lines exhibited SPO-11-generated DSBs and elevated exogenous DNA damage-induced chromosome fragmentation at diakinesis. In addition, the excessive apoptosis in mrg-1 mutants was partially suppressed by loss of the synapsis checkpoint gene pch-2, and a significant number of meiotic nuclei accumulated at the leptotene/zygotene stages with an elevated level of H3K9me2 on the chromatin, which was similarly observed in mutants deficient in the synaptonemal complex, suggesting that the proper progression of chromosome synapsis is likely impaired in the absence of mrg-1. Altogether, these findings suggest that MRG-1 is critical for genomic integrity by promoting meiotic DSB repair and synapsis progression in meiosis.

Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in theC. elegansgerm line

“…S2A). Consistent with MRG-1 promoting the proliferative fate, mrg-1(RNAi) results in a smaller than normal PZ in otherwise wild-type animals (Xu et al, 2012), partially suppresses glp-1(ar202gf ) overproliferation, and slightly enhances the glp-1(bn18ts) smaller PZ phenotype (supplementary material Fig. S3).…”

“…7F). It remains possible that MRG-1 activity is restricted to the PZ through some other mechanism, such as posttranslational modification; however, we consider this unlikely because MRG-1 has been shown to have functions in more proximal regions of the gonad, including maintaining genomic integrity in meiotic cells, silencing X-linked genes and facilitating pairing of homologous chromosomes (Dombecki et al, 2011;Fujita et al, 2002;Olgun et al, 2005;Takasaki et al, 2007;Xu et al, 2012). We propose a model in which MRG-1 sets a Fig.…”

“…We confirm that RFP-1 binds to MRG-1, which is homologous to the mammalian MRG15 (MORF4L1) chromodomain protein. MRG-1 has multiple functions in C. elegans, including facilitating synaptonemal complex-independent pairing of homologous chromosomes (Dombecki et al, 2011), maintaining genomic integrity in germ cells (Xu et al, 2012) and repressing the expression of X-linked genes in the germ line (Takasaki et al, 2007). Additionally, MRG-1 is necessary for proliferation of C. elegans primordial germ cells (Fujita et al, 2002;Takasaki et al, 2007), and loss of MRG15 reduces the proliferation capacity of neural precursor cells in mice (Chen et al, 2009).…”

Maintenance of Genome Integrity by Mi2 Homologs CHD-3 and LET-418 in Caenorhabditis elegans

“…Importantly, loss of CEP-1 does not disrupt other meiotic checkpoint pathways, and the synapsis checkpoint remains intact in cep-1 germ lines (Xu et al, 2012). We therefore tested whether cep-1 inactivation suppressed apoptosis in let-418 and chd-3 germ lines.…”

Depletion of cdc‐25.3, a Caenorhabditis elegans orthologue of cdc25, increases physiological germline apoptosis

“…3A). Activation of egl-1 may also suggest the activation of pch-2 and the synapsis checkpoint because egl-1 was shown to function downstream of pch-2 [44]. These results also suggest that cdc-25.3 may function upstream of these genes to negatively regulate their activities.…”