Weng Katherine A, Jeffreys Charlotte A, Bickel Sharon E
Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
PLoS Genet. 2014 Sep 11;10(9):e1004607. doi: 10.1371/journal.pgen.1004607. eCollection 2014 Sep.
Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during prophase I requires an active rejuvenation program, and provide mechanistic insight into the molecular events that underlie rejuvenation. Gal4/UAS inducible knockdown of the cohesion establishment factor Eco after meiotic S phase, but before oocyte maturation, causes premature loss of meiotic cohesion, resulting in destabilization of chiasmata and subsequent missegregation of recombinant homologs. Reduction of individual cohesin subunits or the cohesin loader Nipped B during prophase I leads to similar defects. These data indicate that loading of newly synthesized replacement cohesin rings by Nipped B and establishment of new cohesive linkages by the acetyltransferase Eco must occur during prophase I to maintain cohesion in oocytes. Moreover, we show that rejuvenation of meiotic cohesion does not depend on the programmed induction of meiotic double strand breaks that occurs during early prophase I, and is therefore mechanistically distinct from the DNA damage cohesion re-establishment pathway identified in G2 vegetative yeast cells. Our work provides the first evidence that new cohesive linkages are established in Drosophila oocytes after meiotic S phase, and that these are required for accurate chromosome segregation. If such a pathway also operates in human oocytes, meiotic cohesion defects may become pronounced in a woman's thirties, not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages at the same rate at which they are lost.
人类卵母细胞中的染色体分离错误是出生缺陷的主要原因，并且随着女性年龄增长，非整倍体妊娠的风险会急剧增加。准确的分离要求姐妹染色单体黏连在人类卵母细胞中保持数十年完整无损，而胎儿期卵母细胞中建立的原始黏连连接逐渐丧失被认为是年龄依赖性分离错误的主要原因。在此，我们证明果蝇卵母细胞在减数分裂前期I期间减数分裂黏连的维持需要一个活跃的恢复程序，并对恢复过程背后的分子事件提供了机制性见解。在减数分裂S期之后但在卵母细胞成熟之前，通过Gal4/UAS诱导敲低黏连建立因子Eco，会导致减数分裂黏连过早丧失，从而导致交叉点不稳定以及随后重组同源染色体的错误分离。在前期I期间减少单个黏连蛋白亚基或黏连蛋白装载因子Nipped B会导致类似缺陷。这些数据表明，Nipped B装载新合成的替代黏连蛋白环以及乙酰转移酶Eco建立新的黏连连接必须在前期I期间发生，以维持卵母细胞中的黏连。此外，我们表明减数分裂黏连的恢复不依赖于前期I早期发生的减数分裂双链断裂的程序性诱导，因此在机制上不同于在G2期营养酵母细胞中鉴定出的DNA损伤黏连重建途径。我们的工作提供了首个证据，即果蝇卵母细胞在减数分裂S期之后会建立新的黏连连接，并且这些连接是准确染色体分离所必需的。如果这样的途径也在人类卵母细胞中起作用，减数分裂黏连缺陷可能在女性三十多岁时变得明显，不是因为原始黏连连接最终失效，而是因为恢复程序不再能够以与它们丧失相同的速率提供新的黏连连接。
