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Failure of homologous synapsis and sex-specific reproduction problems.

Kurahashi H, Kogo H, Tsutsumi M, Inagaki H, Ohye T - Front Genet (2012)

Bottom Line: Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis.This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved.We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

ABSTRACT
The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the prophase of meiosis I. (A) The critical steps that affect chromosomal segregation in meiosis I. During the pre-meiotic S-phase, both maternal (red) and paternal (green) chromosomes are replicated and tightly connected to cohesin complexes (purple circles). Then, two homologous chromosomes undergo pairing, and a synaptonemal complex (pink ladder) is established between them. HR results in the production of at least one obligatory chiasma via crossover. After the disassembly of SC, two homologous chromosomes are pulled in opposite directions to the two spindle poles (gray). (B) Schematic representation of meiotic recombination. Initially, programmed DSBs are induced by SPO11 endonuclease (pink circles). The 5′-ends of the DSBs are then resected and the 3′-protruding single-stranded ends are generated. With the aid of RAD51 or DMC1, the DNA ends produce nucleofilament complexes (blue circles) that facilitate genome-wide homology scanning in order to find homologous chromosomes (red lines). Next, a single-stranded DNA end invades the homologous duplex DNA, forming a D-loop structure. DNA synthesis seals the DSBs and the double Holliday junctions emerge. These Holliday junctions are resolved in one of two ways, crossover (right) or non-crossover (left), with the Holliday junction resolvase (green wedges). (C) Pachytene configuration in balanced carriers of chromosomal translocation. In t(11;22) reciprocal translocation, two translocated chromosomes in concert with two normal counterparts form a quadrivalent to complete synapsis. In a t(14;21) Robertsonian translocation, the translocated chromosome and the two normal counterparts form a trivalent.
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Figure 1: Schematic representation of the prophase of meiosis I. (A) The critical steps that affect chromosomal segregation in meiosis I. During the pre-meiotic S-phase, both maternal (red) and paternal (green) chromosomes are replicated and tightly connected to cohesin complexes (purple circles). Then, two homologous chromosomes undergo pairing, and a synaptonemal complex (pink ladder) is established between them. HR results in the production of at least one obligatory chiasma via crossover. After the disassembly of SC, two homologous chromosomes are pulled in opposite directions to the two spindle poles (gray). (B) Schematic representation of meiotic recombination. Initially, programmed DSBs are induced by SPO11 endonuclease (pink circles). The 5′-ends of the DSBs are then resected and the 3′-protruding single-stranded ends are generated. With the aid of RAD51 or DMC1, the DNA ends produce nucleofilament complexes (blue circles) that facilitate genome-wide homology scanning in order to find homologous chromosomes (red lines). Next, a single-stranded DNA end invades the homologous duplex DNA, forming a D-loop structure. DNA synthesis seals the DSBs and the double Holliday junctions emerge. These Holliday junctions are resolved in one of two ways, crossover (right) or non-crossover (left), with the Holliday junction resolvase (green wedges). (C) Pachytene configuration in balanced carriers of chromosomal translocation. In t(11;22) reciprocal translocation, two translocated chromosomes in concert with two normal counterparts form a quadrivalent to complete synapsis. In a t(14;21) Robertsonian translocation, the translocated chromosome and the two normal counterparts form a trivalent.

Mentions: There is an emerging consensus that the events that occur during the prophase of meiosis I are essential for the proper segregation of homologous chromosomes (Hassold et al., 2000; Handel and Schimenti, 2010). Homologous chromosomes that behave independently during mitotic division have to segregate into two different daughter cells during meiosis I (Figure 1A). To accomplish this process, homologous chromosomes interact with each other, utilizing a specialized pathway known as homologous recombination (HR; Figure 1B). Initially, programmed double-strand-breaks (DSBs) manifest in chromosomal DNA by the action of SPO11 endonuclease at more than 100 sites throughout the entire genome. Activation of the DSB sites is controlled by PRDM9, which encodes a H3K4 methylase. PRDM9 binds to the 13 bp recombination hotspot consensus sequence and facilitates DSB formation via methylation of surrounding histones (Borde et al., 2009; Buard et al., 2009; Baudat et al., 2010; Myers et al., 2010; Parvanov et al., 2010). To correctly repair these DSBs, a subsequent HR pathway is activated and the broken DNA ends begin to look for homologous regions. As the consequence, two homologous chromosomes are brought together in close association, a process known as homolog-pairing. A proteinaceous structure known as the synaptonemal complex (SC) is subsequently formed between the paired homologous chromosomes. This step is called synapsis. The DNA lesions are subsequently repaired via HR with the aid of recombination proteins RAD51 and DMC1. During the final step of HR, a four-stranded DNA structure, the Holliday junction that physically connects the two chromosomes is resolved in one of two ways, crossover or non-crossover. Crossover maintains the physical linkage of the chromosomes (chiasmata) and produces the appropriate bi-oriented tension at the opposite spindle poles during metaphase of meiosis I. Thus, the number and location of the crossover events is strictly regulated (crossover assurance and interference). Meiotic recombination, which is well known as a mechanism that shuffles genetic material in order to produce variation among individuals, is also indispensable for the proper segregation of homologous chromosomes (Kurahashi et al., 2009). Failure of each of these processes triggers cell cycle arrest and the subsequent apoptosis of meiotic cells (Hochwagen and Amon, 2006).


Failure of homologous synapsis and sex-specific reproduction problems.

Kurahashi H, Kogo H, Tsutsumi M, Inagaki H, Ohye T - Front Genet (2012)

Schematic representation of the prophase of meiosis I. (A) The critical steps that affect chromosomal segregation in meiosis I. During the pre-meiotic S-phase, both maternal (red) and paternal (green) chromosomes are replicated and tightly connected to cohesin complexes (purple circles). Then, two homologous chromosomes undergo pairing, and a synaptonemal complex (pink ladder) is established between them. HR results in the production of at least one obligatory chiasma via crossover. After the disassembly of SC, two homologous chromosomes are pulled in opposite directions to the two spindle poles (gray). (B) Schematic representation of meiotic recombination. Initially, programmed DSBs are induced by SPO11 endonuclease (pink circles). The 5′-ends of the DSBs are then resected and the 3′-protruding single-stranded ends are generated. With the aid of RAD51 or DMC1, the DNA ends produce nucleofilament complexes (blue circles) that facilitate genome-wide homology scanning in order to find homologous chromosomes (red lines). Next, a single-stranded DNA end invades the homologous duplex DNA, forming a D-loop structure. DNA synthesis seals the DSBs and the double Holliday junctions emerge. These Holliday junctions are resolved in one of two ways, crossover (right) or non-crossover (left), with the Holliday junction resolvase (green wedges). (C) Pachytene configuration in balanced carriers of chromosomal translocation. In t(11;22) reciprocal translocation, two translocated chromosomes in concert with two normal counterparts form a quadrivalent to complete synapsis. In a t(14;21) Robertsonian translocation, the translocated chromosome and the two normal counterparts form a trivalent.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3376420&req=5

Figure 1: Schematic representation of the prophase of meiosis I. (A) The critical steps that affect chromosomal segregation in meiosis I. During the pre-meiotic S-phase, both maternal (red) and paternal (green) chromosomes are replicated and tightly connected to cohesin complexes (purple circles). Then, two homologous chromosomes undergo pairing, and a synaptonemal complex (pink ladder) is established between them. HR results in the production of at least one obligatory chiasma via crossover. After the disassembly of SC, two homologous chromosomes are pulled in opposite directions to the two spindle poles (gray). (B) Schematic representation of meiotic recombination. Initially, programmed DSBs are induced by SPO11 endonuclease (pink circles). The 5′-ends of the DSBs are then resected and the 3′-protruding single-stranded ends are generated. With the aid of RAD51 or DMC1, the DNA ends produce nucleofilament complexes (blue circles) that facilitate genome-wide homology scanning in order to find homologous chromosomes (red lines). Next, a single-stranded DNA end invades the homologous duplex DNA, forming a D-loop structure. DNA synthesis seals the DSBs and the double Holliday junctions emerge. These Holliday junctions are resolved in one of two ways, crossover (right) or non-crossover (left), with the Holliday junction resolvase (green wedges). (C) Pachytene configuration in balanced carriers of chromosomal translocation. In t(11;22) reciprocal translocation, two translocated chromosomes in concert with two normal counterparts form a quadrivalent to complete synapsis. In a t(14;21) Robertsonian translocation, the translocated chromosome and the two normal counterparts form a trivalent.
Mentions: There is an emerging consensus that the events that occur during the prophase of meiosis I are essential for the proper segregation of homologous chromosomes (Hassold et al., 2000; Handel and Schimenti, 2010). Homologous chromosomes that behave independently during mitotic division have to segregate into two different daughter cells during meiosis I (Figure 1A). To accomplish this process, homologous chromosomes interact with each other, utilizing a specialized pathway known as homologous recombination (HR; Figure 1B). Initially, programmed double-strand-breaks (DSBs) manifest in chromosomal DNA by the action of SPO11 endonuclease at more than 100 sites throughout the entire genome. Activation of the DSB sites is controlled by PRDM9, which encodes a H3K4 methylase. PRDM9 binds to the 13 bp recombination hotspot consensus sequence and facilitates DSB formation via methylation of surrounding histones (Borde et al., 2009; Buard et al., 2009; Baudat et al., 2010; Myers et al., 2010; Parvanov et al., 2010). To correctly repair these DSBs, a subsequent HR pathway is activated and the broken DNA ends begin to look for homologous regions. As the consequence, two homologous chromosomes are brought together in close association, a process known as homolog-pairing. A proteinaceous structure known as the synaptonemal complex (SC) is subsequently formed between the paired homologous chromosomes. This step is called synapsis. The DNA lesions are subsequently repaired via HR with the aid of recombination proteins RAD51 and DMC1. During the final step of HR, a four-stranded DNA structure, the Holliday junction that physically connects the two chromosomes is resolved in one of two ways, crossover or non-crossover. Crossover maintains the physical linkage of the chromosomes (chiasmata) and produces the appropriate bi-oriented tension at the opposite spindle poles during metaphase of meiosis I. Thus, the number and location of the crossover events is strictly regulated (crossover assurance and interference). Meiotic recombination, which is well known as a mechanism that shuffles genetic material in order to produce variation among individuals, is also indispensable for the proper segregation of homologous chromosomes (Kurahashi et al., 2009). Failure of each of these processes triggers cell cycle arrest and the subsequent apoptosis of meiotic cells (Hochwagen and Amon, 2006).

Bottom Line: Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis.This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved.We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

ABSTRACT
The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

No MeSH data available.


Related in: MedlinePlus