洞見 - Computational Biology - # Regulation of Meiotic Double-Strand Break Formation

Genetic and Physical Interactions Reveal Overlapping and Distinct Contributions to Meiotic Double-Strand Break Formation in the Nematode Caenorhabditis elegans

Q: How do the interactions between the different DSB accessory factors change throughout the meiotic prophase to coordinate the timing and placement of DSB formation?

During meiotic prophase, the interactions between the DSB accessory factors play a crucial role in coordinating the timing and placement of DSB formation. The study in C. elegans reveals a complex network of interactions between proteins like DSB-1, DSB-2, DSB-3, HIM-5, XND-1, REC-1, PARG-1, MRE-11, and HIM-17. These interactions are dynamic and change throughout meiotic prophase to ensure the proper regulation of DSB formation. At the early stages of meiotic prophase, proteins like DSB-1, DSB-2, and DSB-3 form a complex that is primarily located on DNA loops. This complex is crucial for the initiation of DSBs. HIM-5 acts as a central player in coordinating the interactions between different accessory factors. It interacts with DSB-1, HIM-17, and XND-1, facilitating the recruitment and assembly of the DSB machinery. Additionally, HIM-5 ensures the retention of X chromosome-specific crossovers, highlighting its role in regulating DSB formation on the X chromosome. As meiotic prophase progresses, the interactions between these accessory factors may change to fine-tune the timing and placement of DSBs. For example, the association of MRE-11 and PARG-1 with the chromosome axis, mediated by HIM-5, may help in maintaining the chromatin architecture conducive to DSB formation. These dynamic interactions between the DSB accessory factors throughout meiotic prophase ensure the precise regulation of DSB formation, essential for successful meiosis.

Q: How do the insights from the C. elegans DSB regulatory complex compare to the models proposed in other organisms, and what are the evolutionary implications of the similarities and differences?

The insights from the C. elegans DSB regulatory complex shed light on the unique mechanisms employed by nematodes to regulate DSB formation during meiosis. While the core machinery involving SPO-11 is conserved across species, the accessory factors in C. elegans show distinct interactions and functions compared to other organisms like yeast and plants. In C. elegans, DSB-1 is identified as a key player that interacts with SPO-11, ensuring the induction of breaks. HIM-5 plays a central role in coordinating the actions of different accessory factors and is essential for X chromosome-specific crossovers. The interactions between DSB-1, DSB-2, DSB-3, and HIM-5 form a complex network that regulates the timing and placement of DSBs. Comparing these findings to models in other organisms, such as yeast and plants, reveals both similarities and differences. In yeast, multiple accessory factors interact with Spo11 to regulate DSB formation, similar to the interactions observed in C. elegans. However, the specific roles and interactions of these factors may vary between species. In plants, a similar model for DSB induction as in yeast has been proposed, suggesting some conservation in the regulatory mechanisms. The evolutionary implications of these similarities and differences suggest that while the core machinery for DSB formation is conserved, the specific regulatory mechanisms have diverged during evolution to adapt to the unique requirements of each organism. Understanding these differences can provide insights into the evolutionary processes shaping meiotic regulation and genome stability across different species.

Q: What are the potential mechanisms by which HIM-5 ensures the X chromosome-specific regulation of DSB formation?

HIM-5 plays a crucial role in ensuring X chromosome-specific regulation of DSB formation in C. elegans. Several potential mechanisms contribute to this specificity: Transcriptional Regulation: HIM-5 may regulate the expression of genes involved in DSB formation specifically on the X chromosome. Interactions between HIM-5 and other accessory factors like XND-1 and HIM-17 could modulate the transcription of genes essential for DSB induction on the X chromosome. Chromatin Architecture: HIM-5 could influence the chromatin structure on the X chromosome, creating a microenvironment conducive to DSB formation. This chromatin remodeling may be specific to the X chromosome, ensuring the proper initiation of breaks in this region. Protein-Protein Interactions: HIM-5 interacts with DSB-1, HIM-17, and XND-1, forming a network of interactions that are crucial for X chromosome-specific DSB regulation. These interactions may facilitate the recruitment and assembly of the DSB machinery specifically on the X chromosome. Timing of Breaks: HIM-5 may play a role in coordinating the timing of DSB formation on the X chromosome, ensuring that breaks occur at the appropriate stage of meiotic prophase. This temporal regulation could contribute to the X chromosome-specificity of DSB formation. By integrating these mechanisms, HIM-5 acts as a central player in orchestrating X chromosome-specific regulation of DSB formation, ensuring the proper exchange of genetic material and maintenance of genome stability during meiosis in C. elegans.

核心概念

Genetic and physical interactions between the Spo11 accessory factors in the nematode Caenorhabditis elegans reveal a complex network that coordinates the timing, placement, and number of meiotic double-strand breaks, with HIM-5 playing a central role as a linchpin between the different sub-complexes.

摘要

The content provides a detailed analysis of the genetic and physical interactions between the Spo11 accessory factors that regulate meiotic double-strand break (DSB) formation in the nematode Caenorhabditis elegans.

Key highlights:

HIM-5 is the essential factor for meiotic breaks on the X chromosome and interacts with multiple accessory factors, serving as a linchpin to coordinate the timing, placement, and number of DSBs.
DSB-1 is the only known accessory factor that directly interacts with SPO-11, the enzyme that catalyzes DSB formation, and this interaction is mediated by distinct domains of DSB-1.
Genetic epistasis analysis defines four groups of accessory factors that contribute to DSB/crossover formation through overlapping and distinct mechanisms.
XND-1 and HIM-17 physically interact and regulate the expression of HIM-5, linking chromatin structure to DSB induction.
The model proposes that the DSB regulatory complex in C. elegans shares some similarities with the complexes described in yeast and plants, but also exhibits unique features.

The summary provides a comprehensive overview of the key insights and mechanisms underlying meiotic DSB regulation in C. elegans, as revealed by the genetic, biochemical, and cytological analyses presented in the content.

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統計資料

"DSB-1 and DSB-2 are distant paralogs, and they are both orthologs of the budding yeast Rec114 protein."
"DSB-3 is an ortholog of yeast Mei4."
"Mutations in dsb-1 and dsb-3 are required for all meiotic breaks."
"Ectopic expression of HIM-5 can substantially rescue both the autosomal and X chromosomal defects of him-17 null mutations."
"In dsb-1 mutants, HIM-5 localizes to cytoplasmic puncta at mid-pachytene, suggesting that DSB-1 (and/or its DSB-promoting function) is required to retain HIM-5 in meiotic nuclei."

引述

"HIM-5 appears to be central to DSB/CO formation on the X chromosome and mutations in dsb-1 and dsb-3 are required for all meiotic breaks."
"DSB-1 is the only known accessory factor that directly interacts with SPO-11, the enzyme that catalyzes DSB formation, and this interaction is mediated by distinct domains of DSB-1."
"XND-1 and HIM-17 physically interact and regulate the expression of HIM-5, linking chromatin structure to DSB induction."

從以下內容提煉的關鍵洞見

Genetic and physical interactions reveal overlapping and distinct contributions to meiotic double-strand break formation in C. elegans

by Raices,M., B... 於 www.biorxiv.org 02-28-2024

https://www.biorxiv.org/content/10.1101/2024.02.23.581796v2

深入探究

How do the interactions between the different DSB accessory factors change throughout the meiotic prophase to coordinate the timing and placement of DSB formation?

During meiotic prophase, the interactions between the DSB accessory factors play a crucial role in coordinating the timing and placement of DSB formation. The study in C. elegans reveals a complex network of interactions between proteins like DSB-1, DSB-2, DSB-3, HIM-5, XND-1, REC-1, PARG-1, MRE-11, and HIM-17. These interactions are dynamic and change throughout meiotic prophase to ensure the proper regulation of DSB formation.
At the early stages of meiotic prophase, proteins like DSB-1, DSB-2, and DSB-3 form a complex that is primarily located on DNA loops. This complex is crucial for the initiation of DSBs. HIM-5 acts as a central player in coordinating the interactions between different accessory factors. It interacts with DSB-1, HIM-17, and XND-1, facilitating the recruitment and assembly of the DSB machinery. Additionally, HIM-5 ensures the retention of X chromosome-specific crossovers, highlighting its role in regulating DSB formation on the X chromosome.
As meiotic prophase progresses, the interactions between these accessory factors may change to fine-tune the timing and placement of DSBs. For example, the association of MRE-11 and PARG-1 with the chromosome axis, mediated by HIM-5, may help in maintaining the chromatin architecture conducive to DSB formation. These dynamic interactions between the DSB accessory factors throughout meiotic prophase ensure the precise regulation of DSB formation, essential for successful meiosis.

How do the insights from the C. elegans DSB regulatory complex compare to the models proposed in other organisms, and what are the evolutionary implications of the similarities and differences?

The insights from the C. elegans DSB regulatory complex shed light on the unique mechanisms employed by nematodes to regulate DSB formation during meiosis. While the core machinery involving SPO-11 is conserved across species, the accessory factors in C. elegans show distinct interactions and functions compared to other organisms like yeast and plants.
In C. elegans, DSB-1 is identified as a key player that interacts with SPO-11, ensuring the induction of breaks. HIM-5 plays a central role in coordinating the actions of different accessory factors and is essential for X chromosome-specific crossovers. The interactions between DSB-1, DSB-2, DSB-3, and HIM-5 form a complex network that regulates the timing and placement of DSBs.
Comparing these findings to models in other organisms, such as yeast and plants, reveals both similarities and differences. In yeast, multiple accessory factors interact with Spo11 to regulate DSB formation, similar to the interactions observed in C. elegans. However, the specific roles and interactions of these factors may vary between species. In plants, a similar model for DSB induction as in yeast has been proposed, suggesting some conservation in the regulatory mechanisms.
The evolutionary implications of these similarities and differences suggest that while the core machinery for DSB formation is conserved, the specific regulatory mechanisms have diverged during evolution to adapt to the unique requirements of each organism. Understanding these differences can provide insights into the evolutionary processes shaping meiotic regulation and genome stability across different species.

What are the potential mechanisms by which HIM-5 ensures the X chromosome-specific regulation of DSB formation?

HIM-5 plays a crucial role in ensuring X chromosome-specific regulation of DSB formation in C. elegans. Several potential mechanisms contribute to this specificity:

Transcriptional Regulation: HIM-5 may regulate the expression of genes involved in DSB formation specifically on the X chromosome. Interactions between HIM-5 and other accessory factors like XND-1 and HIM-17 could modulate the transcription of genes essential for DSB induction on the X chromosome.

Chromatin Architecture: HIM-5 could influence the chromatin structure on the X chromosome, creating a microenvironment conducive to DSB formation. This chromatin remodeling may be specific to the X chromosome, ensuring the proper initiation of breaks in this region.

Protein-Protein Interactions: HIM-5 interacts with DSB-1, HIM-17, and XND-1, forming a network of interactions that are crucial for X chromosome-specific DSB regulation. These interactions may facilitate the recruitment and assembly of the DSB machinery specifically on the X chromosome.

Timing of Breaks: HIM-5 may play a role in coordinating the timing of DSB formation on the X chromosome, ensuring that breaks occur at the appropriate stage of meiotic prophase. This temporal regulation could contribute to the X chromosome-specificity of DSB formation.

By integrating these mechanisms, HIM-5 acts as a central player in orchestrating X chromosome-specific regulation of DSB formation, ensuring the proper exchange of genetic material and maintenance of genome stability during meiosis in C. elegans.