Meiotic recombination checkpoint

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The meiotic recombination checkpoint monitors the meiotic recombination during meiosis, and blocks the entry into metaphase I if the recombination is not efficiently processed. Meiotic recombination contributes to the cells in three different ways. First, to achieve proper segregation, each pair of homologous chromosomes must be linked to each other to maintain a certain level of tension between them. Such tension is supposed to help the assembly of spindles and generally depends on meiotic recombination. Secondly, meiotic recombination increases the genetic diversity of gametes, making them readily adapt to new environment. Thirdly, meiotic recombination is a DNA repair process that removes damages from the DNA passed on to gametes.


See caption
Spo11 catalyzes a double strand break in one of the two homologous chromosomes to induce meiotic recombination. DSB-dependent meiotic recombination checkpoint monitors the repair of these DSBs while DSB-independent meiotic recombination checkpoint examines the asynapsis of each homolog pair which is the consequence of uncompleted DSB induction.

Generally speaking, the cell cycle regulation of meiosis is similar to that of mitosis. As in the mitotic cycle, these transitions are regulated by combinations of gene regulatory factors, cyclin-Cdk complex and the APC.[1] The first major regulatory transition occurs in late G1, when the Start of meiotic cycle is activated by Ime1 instead of Cln3/Cdk1 in mitosis. The second major transition occurs at the entry into metaphase I. The main purpose of this step is to make sure that DNA replication has completed without error so that spindle pole bodies can separate. The event is triggered by the activation of M-Cdk in late prophase I. Then the spindle assembly checkpoint examines the attachment of microtubules at kinetochores and APCCdc20 can initiate the metaphase I. The special chromosome separation in meiosis, homologous chromosomes separation in meiosis I and chromatids separation in meiosis II, requires special tension between homologous chromatids and non-homologous chromatids for distinguishing microtubule attachment and it relies on the programmed DNA double strand break (DSB) and repair in prophase I. Therefore meiotic recombination checkpoint can be a kind of DNA damage response at specific time spot. On the other hand, the meiotic recombination checkpoint also makes sure that meiotic recombination does happen in every pair of homologs.

DSB-dependent pathway[edit]

The abrupt onset of M-Cdk in late prophase I depends on the positive transcription regulation feedback loop consisting of Ime2, Ndt80 and Cdk/cyclin complex. However the activation of M-Cdk is controlled by the general phosphorylation switch Wee1/Cdc25. Wee1 activity is high in early prophase I and the accumulation of Cdc25 activates M-Cdk by direct phosphorylation and marking Wee1 to be degraded. Meiotic recombination may begin with a double-strand break, either induced by Spo11[2] or by other endogenous or exogenous causes of DNA damage. These DNA breaks must be repaired before metaphase I. and these DSBs must be repaired before metaphase I. The cell monitor these DSBs via ATM pathway, in which Cdc25 is suppressed when DSB lesion is detected. This pathway is the same as classical DNA damage response and is the part we know the best in meiotic recombination checkpoint.

DSB-independent pathway[edit]

The DSB-independent pathway was proposed when people studied spo11 mutant cells in some species and found that these Spo11 cells could not process to metaphase I even in the absence of DSB.[3] The direct purpose of these DSBs is to help with the condensation of chromosomes. Even though the initial homolog paring in early leptotene is just random interactions, the further progression into presynaptic alignment depends on the formation of double strand breaks and single strand transfer complexes.[1][4] Therefore the unsynapsed chromosomes in Spo11 cells can be a target of checkpoint. An AAA–adenosine triphosphatase (AAA-ATPase) was found to be essential in this pathway.[5] but the mechanism is not yet clear. Some other studies also drew sex body formation into attention, and the signaling could be either structure based or transcription regulation such as meiotic sex chromosome inactivation.[6][7] Under this cascade, failure to synapse will maintain the gene expression from sex chromosomes and some products may inhibit cell cycle progression. Meiotic sex chromosome inactivation only happens in male, which may partially be the reason why only Spo11 mutant spermatocytes but not oocytes fail to transition from prophase I to metaphase I.[3][8] However the asynapsis does not happen only within sex chromosomes, and such transcription regulation was suspended until it was further expanded to all the chromosomes as meiotic silencing of unsynapsed chromatin,[9] but the effector gene is not found yet.

Meiotic checkpoint protein kinases CHEK1 and CHEK2[edit]

The central role in meiosis of human and mouse CHEK1 and CHEK2 and their orthologs in Saccharomyces cerevisiae, Caenorhabditis elegans, Schizosaccharomyces pombe and Drosophila has been reviewed by MacQueen and Hochwagen[10] and Subramanian and Hochwagen.[11] During meiotic recombination in human and mouse, CHEK1 protein kinase is important for integrating DNA damage repair with cell cycle arrest.[12] CHEK1 is expressed in the testes and associates with meiotic synaptonemal complexes during the zygonema and pachynema stages.[12] CHEK1 likely acts as an integrator for ATM and ATR signals and in monitoring meiotic recombination.[12] In mouse oocytes CHEK1 appears to be indispensable for prophase I arrest and to function at the G2/M checkpoint.[13]

CHEK2 regulates cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development.[14] Although CHEK2 is a down stream effector of the ATM kinase that responds primarily to double-strand breaks it can also be activated by ATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mouse, CHEK2 is essential for DNA damage surveillance in female meiosis. The response of oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates p53 and p63 proteins.[15]

In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and apoptosis. The Drosophila CHEK2 ortholog mnk and the p53 ortholog dp53 are required for much of the cell death observed in early oogenesis when oocyte selection and meiotic recombination occur.[16]

See also[edit]


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