State Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Cell Res. 2012 May;22(5):886-902. doi: 10.1038/cr.2012.2. Epub 2012 Jan 3.
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.
在减数分裂细胞分裂过程中,需要正确的染色体联会和 DNA 双链断裂 (DSB) 的准确修复,以维持基因组的完整性,否则会导致细胞凋亡或减数分裂缺陷。减数分裂染色体联会、DSB 修复和细胞凋亡的机制尚未完全阐明。在这里,我们报告染色质域蛋白 MRG-1 是秀丽隐杆线虫减数分裂中基因组完整性的重要因素。MRG-1 功能丧失会导致生殖细胞凋亡显著增加,这种增加部分受到影响 DNA 损伤检查点基因的突变抑制。一致地,mrg-1 突变体生殖系表现出 SPO-11 产生的 DSB 和外源性 DNA 损伤诱导的在减数分裂双线期染色体碎片化增加。此外,mrg-1 突变体中的过度凋亡部分被联会检查点基因 pch-2 的缺失所抑制,并且大量减数分裂核在细线期/合线期积累,染色质上的 H3K9me2 水平升高,这在联会复合体缺陷突变体中也观察到,这表明在缺乏 mrg-1 的情况下,染色体联会的正常进展可能受到损害。总之,这些发现表明,MRG-1 通过促进减数分裂 DSB 修复和联会进展,对减数分裂中的基因组完整性至关重要。