A conserved mechanism known as homologous recombination repairs multiple DNA lesions including double-strand breaks. The homologous recombination system represents a DNA repair mechanism that copies homologous DNA sequences from an intact donor template to restore integrity. The exchange between two homologous DNA strands requires the activity of RecA family recombinases like Rad51 and Dmc1 which serve as eukaryotic equivalents of the prokaryotic RecA protein. Swi5 binds with Sfr1C to make a complex while both Swi5 and Sfr1 proteins fulfill crucial functions throughout meiosis. Swi5 and Sfr1 mutations lead to lower homologous recombination activity in mitotic and meiotic cells while making them more susceptible to multiple DNA damaging agents.
The evolutionarily preserved Swi5-Sfr1 complex functions as a critical element in homologous recombination which preserves genomic stability. The precise functional roles of Swi5 and Sfr1 phosphorylation have yet to be established. The phosphorylated Swi5-Sfr1 complex serves as an essential component of homologous recombination (HR) which is particularly significant for fixing DNA double-strand breaks (DSBs).
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Introduction to Swi5-Sfr1 complex
- The conserved proteins Swi5 and Sfr1 exist throughout eukaryotic species including yeast and mammals.
- The Swi5-Sfr1 heterodimer complex functions during several stages of homologous recombination repair.
- The Swi5-Sfr1 complex interacts with Rad51 which serves as the central recombinase enzyme in homologous recombination.
| Function |
Function |
| Promote Rad51 nucleosome formation |
Stabilizes the binding of Rad51 to ssDNA |
| Activate Rad51 ATPase activity |
Improve DNA strand exchange efficiency |
| Regulate protein interactions |
Regulated by phosphorylation, improving functional dynamics |
| DNA damage repair response |
Plays a key role in DSB repair |
Mechanism of Action in Homologous Recombination
Factor Promoting Rad51-mediated DNA Strand Exchange
The protein complex Swi5-Sfr1 enhances the assembly of Rad51 nucleoprotein filaments through its ability to strengthen Rad51's attachment to single-stranded DNA. This factor boosts Rad51's DNA strand exchange capability while serving as a co-factor for Rad51.
Activates the ATPase Activity of Rad51
Swi5-Sfr1 stimulates Rad51's ATP hydrolysis ability which plays a critical role during DNA strand exchange and the separation of complexes.
Anti-effects of Rad51 Inhibitors
Swi5-Sfr1 can negate the impact of Rad51 inhibitors such as Srs2 under specific conditions while preserving Rad51 functionality.
Regulation of Swi5-Sfr1 Function by Phosphorylation
Phosphorylation is an important regulator of the activity of the Swi5-Sfr1 complex, which has the following effects:
Cell Cycle-dependent Regulation
Some phosphorylation events may depend on the cell cycle stage (such as S phase or G2 phase) to ensure that homologous recombination occurs at the appropriate time.
Role in DNA Damage Response
After DNA damage occurs, the phosphorylation state of Swi5-Sfr1 may change rapidly to adapt to the repair needs.
Phosphorylation of the Swi5-Sfr1 complex in meiosis
The phosphorylation sites are located at the N-terminus of Sfr1, which is intrinsically disordered.
Specific Expression and Phosphorylation in Meiosis
This phosphorylation is usually mediated by meiosis-specific kinases (such as Cdc2/Cdk1, Mek1 (in yeast), etc.).
Regulating Temporal and Spatial Activity
- Phosphorylation may be part of a temporal control mechanism that ensures that the Swi5-Sfr1 complex only functions during the active phase of homologous chromosome pairing and exchange.
- For example, during prophase I of meiosis, phosphorylation enhances its ability to bind to Rad51 and promotes cross-chromosomal recombination.
Functional Coupling with Rad51/Dmc1
- In meiosis, in addition to Rad51, there is also a meiosis-specific recombinase Dmc1.
- In some organisms, phosphorylated Sfr1 prefers to support Rad51 activity.
- By regulating the phosphorylation state, Rad51 can also be prevented from excessively interfering with Dmc1-dominated meiotic recombination at inappropriate times.
References
- Argunhan, B., et al. The differentiated and conserved roles of Swi5‐Sfr1 in homologous recombination. FEBS letters. 2017, 591(14): 2035-2047.
- Lu, C., et al. Swi5–Sfr1 stimulates Rad51 recombinase filament assembly by modulating Rad51 dissociation. Proceedings of the National Academy of Sciences. 2018, 115(43): 10059-10068.
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