24.3: DNA Recombination

Search Fundamentals of Biochemistry

Learning Goals 

 

(Learning goals written by Claude, Sonnet 4.6, Anthropic)

Mechanisms of Homologous Recombination and DSB Repair

• Describe the sequential molecular steps of homologous recombination following a double-strand break (DSB): explain how 5′-end resection generates 3′ ssDNA overhangs, how RPA initially coats the ssDNA and is replaced by Rad51/Dmc1 recombinase filaments that mediate strand invasion into a homologous duplex to form a D-loop, how DNA synthesis extends the invading 3′ end, and how second-end capture generates a double Holliday junction (dHJ) intermediate that can be resolved to either crossover or noncrossover products.
• Distinguish between the two main DSB repair outcomes: explain how the SDSA (synthesis-dependent strand annealing) pathway generates exclusively noncrossover products by ejecting the invading strand after synthesis and reannealing it with the second broken end—thereby restoring the original sequence without reciprocal exchange—while the dHJ pathway, stabilized by ZMM proteins and resolved by MutLγ/Exo1, generates crossovers involving reciprocal exchange of chromosomal segments, and explain why SDSA is preferred in somatic cells to avoid loss of heterozygosity.
• Compare homologous recombination with alternative DSB repair pathways: explain how NHEJ repairs unresected or minimally resected DSBs in a template-independent manner, how MMEJ uses microhomology flanking the break ends, and how SSA (single-strand annealing) requires homology between the two resected ends on the same molecule—and explain why the choice among these pathways is controlled primarily by the extent of 5′ resection at the break ends.

Meiotic Recombination, the Synaptonemal Complex, and Genetic Variation

• Explain how programmed DSBs initiate meiotic recombination: describe how the Spo11 protein—homologous to the catalytic subunit of archaeal Topo VIA type II topoisomerase—forms a transient covalent 5′-phosphotyrosyl linkage at DSB ends, how MRX (Mre11-Rad50-Xrs2)/Sae2 endonucleolytic cleavage releases Spo11 attached to a short oligonucleotide, and how subsequent 5′→3′ exonuclease resection generates the ssDNA tails that initiate recombinase filament assembly.
• Describe the structure and assembly of the synaptonemal complex (SC): explain how lateral elements (containing SYCP2 and SYCP3) form along each chromosome axis during leptotene, how transverse filaments (primarily SYCP1) connect the lateral elements of homologous chromosomes during zygotene, how the central element (SYCE1, SYCE2, SYCE3, TEX12) completes the tripartite structure during pachytene, and explain how the SC biases DSB repair toward the homologous chromosome rather than the sister chromatid to ensure interhomolog recombination and productive crossover formation.
• Explain the biological significance of crossovers and chiasmata in meiosis: describe how chiasmata—the cytological manifestations of crossovers—provide the physical connections between homologous chromosomes that are required for bipolar attachment to the meiotic spindle and accurate segregation at meiosis I; explain why at least one crossover per homolog pair is obligatory for proper segregation; and explain how the combination of crossovers and sister chromatid cohesion ensures that homologs remain attached until their separation at anaphase I while sister chromatids remain joined until meiosis II.
• Describe the genetic outcomes of meiosis and how they contribute to evolutionary diversity: explain how meiosis I reduces the diploid (2n) genome to the haploid (n) state through homolog segregation, how meiosis II separates sister chromatids to produce four genetically unique haploid gametes, and explain how two independent sources of genetic variation—random assortment of non-homologous chromosomes at meiosis I and crossover recombination during meiotic prophase I—generate the genetic diversity among gametes that drives population-level adaptation and evolution.

Homologous Recombination

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA, as in cellular organisms, but may also be RNA in viruses). As noted in section 25.2, this process is widely used by cells to accurately repair harmful breaks in both DNA strands, known as double-strand breaks (DSBs), via homologous recombination repair (HRR). Homologous recombination also produces new combinations of DNA sequences during meiosis, the process by which eukaryotes produce gamete cells, such as sperm and egg cells in animals. These new combinations of DNA represent genetic variation in offspring, which in turn enables populations to adapt during evolution. Homologous recombination is also used in horizontal gene transfer to exchange genetic material between different strains and species of bacteria and viruses.

Although homologous recombination varies widely among organisms and cell types, in double-stranded DNA (dsDNA), most forms follow the same basic steps. After a double-strand break occurs, sections of DNA around the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" a similar or identical DNA molecule that is not broken. After strand invasion, the further sequence of events may follow either of two main pathways discussed below (see Models): the DSBR (double-strand break repair) pathway or the SDSA (synthesis-dependent strand annealing) pathway. Homologous recombination during DNA repair often yields non-crossover products, effectively restoring the damaged DNA molecule to its original state before the double-strand break.

There are several different ways to repair DSB as illustrated in Figure \(\PageIndex{1}\). The broken (or resected) DNA with a double-stranded break must find and come together (synapse) with homologous donor DNA, and then invade (or intertwine) with the donor DNA. The repair can then ensue. In somatic cells that undergo mitosis, not meiosis, the preferred donor is the sister chromatid (the copy of one chromosome made during cell division), not the homologous chromosome (from the diploid cell). Variants include the synthesis-dependent strand annealing pathway (SDSA). Other variants include nonhomologous end-joining (NHEJ), microhomology-mediated end-joining (MMEJ), and double Holliday junction (dHJ).

Figure \(\PageIndex{1}\): Model for the repair of DNA double-strand breaks by homologous recombination in somatic cells. Wright et al. J. Biol. Chem. (2018) 293(27) 10524 –10535. Creative Commons Attribution (CC BY 4.0)

When a DNA double-strand break (DSB) occurs in a DNA molecule, repair can proceed through multiple pathways, primarily controlled by end resection. NHEJ can repair unresected or minimally resected double-strand breaks (DSBs) in a template-independent manner. MMEJ and single-strand annealing (SSA) rely on different extents of homology between the two DSB ends for repair, independent of a donor molecule.  Homologous recombination proceeds as shown in the figure using a homologous donor DNA. Most of the extended D-loops in somatic cells are disrupted and subsequently repaired by SDSA. The result of the repair by SDSA is always a noncrossover outcome, thus avoiding the loss of heterozygosity produced by somatic crossovers. SDSA occurs through the disruption of the extended D-loop and annealing of the newly synthesized DNA to the second end of the broken molecule. Alternatively, the newly synthesized strand may invade the second end. The extended D-loop can also undergo second-end capture or invasion, forming a double Holliday junction (dHJ). This may result in either a crossover or a noncrossover outcome. Invasion by the second break end makes dHJ formation and, hence, crossover outcomes more likely in another model of crossover generation. dHJs can be dissolved into noncrossovers by the concerted action of the Sgs1–Top3–Rmi1 complex to migrate the two junctions toward each other and then decatenate the strands of the hemicatenane by the Top3 topoisomerase activity. Each colored line represents a DNA strand, and the dotted lines indicate DNA synthesis.

In the process of homologous recombination, a key intermediate is the Holliday junction, named after Robin Holliday, who discovered it. It consists of branched nucleic acid with four double-stranded arms joined. A Holliday junction is depicted as the crossing of red and blue strands in the middle of Figure 1, labeled "Nascent D-loop." Additionally, one is also visible in the Extended D-loop, located just below it. A double Holiday junction is seen in the middle of the right-hand section. Two views of Holiday junctions are shown in Figure \(\PageIndex{2}\).

By Донор - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/inde...curid=48470765

By Antony-22 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/inde...curid=38557614

Figure \(\PageIndex{2}\). Two views of holiday junctions. The left-hand panel displays the primary and secondary sequences, as well as some tertiary (3D) aspects, of the base-stacking conformational isomers of the Holliday junction. The bases nearest to the junction point determine which stacked isomer dominates.

Figure \(\PageIndex{3}\) shows an interactive iCn3D model of the structure of the Holliday junction intermediate in Cre-loxP site-specific recombination (3CRX).

Figure \(\PageIndex{3}\): Structure of the Holliday junction intermediate in Cre-loxP site-specific recombination (3CRX). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...CQeGXUXiQa4AY8

The alpha carbon backbone of the four Cre recombinase monomers in the tetramer is shown in red. The DNA is nearly planar, with a twofold-symmetric DNA intermediate that resembles a square and a stacked Holliday junction in the unbound state.

Homologous recombination is conserved across all three domains of life as well as DNA and RNA viruses, suggesting that it is a nearly universal biological mechanism. The discovery of genes for homologous recombination in protists—a diverse group of eukaryotic microorganisms—has been interpreted as evidence that meiosis emerged early in the evolution of eukaryotes. Since their dysfunction has been strongly associated with increased susceptibility to several types of cancer, the proteins that facilitate homologous recombination are topics of active research. Homologous recombination is also used in gene targeting, a technique that introduces genetic changes into target organisms. For their development of this technique, Mario Capecchi, Martin Evans, and Oliver Smithies were awarded the 2007 Nobel Prize for Physiology or Medicine; Capecchi[3] and Smithies[4] independently discovered applications to mouse embryonic stem cells, however, the highly conserved mechanisms underlying the DSB repair model, including uniform homologous integration of transformed DNA (gene therapy), were first shown in plasmid experiments by Orr-Weaver, Szostack, and Rothstein.

Before the beginning of meiosis, the replication of the DNA is required to form sister chromatids, as shown in Step 1 in Figure \(\PageIndex{4}\). Once replicated, the DNA will condense and begin meiosis. As the cells enter metaphase of meiosis, homologous chromosomes pair (Step 2). When homologous chromosomes pair, they can undergo genetic recombination to form new chromosomal arrangements distinct from the parental chromosomes (Step 3). Once the recombination process is complete, the homologous chromosomes are segregated into two distinct daughter cells (Step 4). This is called Meiosis I. At this stage, the chromosomes have been reduced from diploid to haploid; however, each chromosome set is still paired with its sister chromatid and must undergo a second round of cell division to produce the final set of four gametes (Step 5). This process is known as Meiosis II and results in the formation of four haploid gametes that are genetically distinct.

Figure \(\PageIndex{4}\): The Process of Meiosis. Peter Coxhead

During meiosis, cell division produces the gametes, or reproductive cells, of an organism, specifically egg and sperm cells. Meiosis reduces the genome from the 2n (diploid) state to the 1n (haploid) state. As you can see in Figure 25.3.1, the process of meiotic division results in the generation of four genetically unique haploid cells and involves the pairing of homologous chromosomes during metaphase of meiosis. In humans, the meiotic process results in the production of four viable sperm cells in males and a single viable egg in females. The other three cells produced in the female during meiotic division are termed polar bodies and are very small, lacking sufficient cytoplasmic components to survive. They get reabsorbed into the body. In either case, the resulting egg or sperm cell carries a single copy of the genome and is haploid.

It is during meiosis that homologous recombination occurs in a controlled manner, introducing genetic variation into the resulting gametes. As a result, each egg and sperm cell has a unique genetic makeup that is a mixture of both parental genome copies.

Proper segregation during meiosis requires that crossovers and sister chromatid cohesion connect homologs. To generate crossovers, numerous double-strand breaks (DSBs) are introduced throughout the genome by the conserved Spo11 endonuclease. DSB formation and repair are tightly regulated to ensure that homologous chromosomes contain at least one crossover and that no DSBs remain before meiosis I segregation. The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes double-strand break (DSB) formation and biases DSB repair toward homologous chromosomes rather than back to sister chromatids, ensuring that genetic recombination occurs. Synapsis, the pairing of homologous chromosomes, occurs when a specific recombination pathway successfully establishes stable interhomolog connections.

Formation of the Synaptonemal Complex

In the 1950s, electron microscopists discovered an evolutionarily conserved, meiosis-specific structure formed between homologous chromosomes, unique to prophase I, called the SC, as shown in Figure \(\PageIndex{5}\). The SC physically connects homologs during prophase I and is removed before metaphase I, when homologs are instead connected by crossovers and sister chromatid cohesion. What is the function of the SC? Decades of research have demonstrated that this elaborate chromosomal structure is crucial for regulating recombination, the process by which crossovers are formed.

Figure \(\PageIndex{5}\): The relationship of DSB formation to synapsis in different situations. Hollingsworth, N.M. (2020) Genes and Dev 34:1562-1564.

Panel (A) shows the synaptonemal complex. When chromosomes form synapses, recombination intermediates contain double Holliday junctions, which are indicated by intersecting loops. When cells exit the pachytene stage of meiotic prophase, chromosomes fully synapse, Holliday junctions are resolved to form crossovers, and the SC is disassembled. Synapses greatly reduce DSB formation but are not entirely abolished until cells exit pachynema.

Panel (B) shows that the sequence diversity between homologous chromosomes largely inhibits recombination and synapsis, resulting in persistent DSB formation.

Panel (C) shows that in the absence of the central element, the transverse filament is not assembled, resulting in chromosomes that lack the central region. Recombination intermediates containing double Holliday junctions are still formed, but DSB formation is not down-regulated. 

SC formation begins with the condensation of sister chromatids along meiosis-specific protein cores to make axial elements. Axial elements from homologous chromosomes are “zippered” together by the insertion of the central region. (Note that after synapsis, axial elements are called lateral elements (Panel A above). The central region is comprised of (1) transverse filaments located perpendicular to the lateral elements, and (2) the central element, which runs parallel to the lateral elements midway through the central region.

Assembly of the SC is initiated in the early stage of meiotic prophase I, which is commonly divided into five substages (leptotene, zygotene, pachytene, diplotene, and diakinesis). For proper assembly of the SC followed by the correct pairing of the homologous chromosome, lateral elements (LEs), which are composed of two main proteins (SYCP2 and SYCP3) should be formed along each chromosome at the initial stage, during leptotene. Later, the two LEs associate with the linker part, known as the transverse filaments (TFs). TFs are primarily composed of the protein SYCP1. The central element (CE), which is composed of SYCE1, SYCE2, SYCE3, and TEX12, then connects to the LEs through the TFs, as shown in Figure \(\PageIndex{6}\).

Figure \(\PageIndex{6}\): Organization of the Synaptonemal Complex. Image from: Seo, E.K., et al. (2016) PLOS one: DOI 10.1371

The lateral elements complete their pairing during the zygotene stage, leading to the formation of the tripartite SC structure seen during the pachytene stage of the first meiotic prophase, as shown in Figure \(\PageIndex{7}\) and Figure \(\PageIndex{8}\). This occurs in both males and females during gametogenesis.

Figure \(\PageIndex{7}\): Schematic of the Synaptonemal Complex at Different Stages During Prophase I. Image from: Daniel Wells

Figure \(\PageIndex{8}\): The Synaptonemal Complex. The Public Library of Science

Panel (A) shows a model of the SC. Lateral elements (light blue rods) of homologous chromosomes align and synapse together via a meshwork of transverse filaments (black lines) and longitudinal filaments (dark blue rods). The longitudinal filaments are collectively referred to as the “central element” of the SC. Ellipsoidal structures called recombination nodules (gray ellipsoid) are constructed in the central region of the SC. As their name implies, recombination nodules are believed to facilitate meiotic recombination, also known as crossing over. The chromatin (red loops) of each homolog is attached to its corresponding lateral element. Because there are two “sister chromatids” in each homolog, two loops are shown extending laterally from each point along a lateral element.

Panel (B) Top shows a set of tomato SCs. Chromatin “sheaths” are visible around each SC, showing two tomato SCs. The chromatin has been stripped from the SCs, allowing the SC details to be observed. Each SC has a kinetochore, a ball-like structure, at its centromere. Recombination nodules, ellipsoidal structures found on the central regions of SCs, mark the sites of crossover events (see inset).

Zygotene is the substage in which synapsis between homologous chromosomes begins. It is also known as Zygonema. This synapse can form along the chromosomes, allowing numerous points of contact called 'synaptonemal complex', which can be compared to a zipper structure due to the coils of chromatin. The SC facilitates synapsis by holding the aligned chromosomes together. After the homologous pairs synapse, they are either called tetrads or bivalents. Bivalents are more commonly used at an advanced level as they are a better choice due to similar names for similar states (a single homolog is a 'univalent', and three homologs are a 'trivalent').

Once the synapse is formed, it is called a bivalent (where a chromatid of one pair is synapsed/attached to the chromatid in a homologous chromosome, and crossing over can occur. Subsequently, the synapses snap, completing the crossover of genetic information. As a result, genetic variation has increased significantly due to the exchange of genetic material between mother and father across chromosomes. The two sister chromatids separate, but the homologous chromosomes remain attached. This makes the complex look much thicker. The SC is complete, allowing chiasma to form. This is what allows crossing over of alleles to occur, as this process only happens over a small region of the chromosomes.

The chiasma is a structure that forms between a pair of homologous chromosomes by crossover recombination and physically links the homologous chromosomes during meiosis, as shown in Figure \(\PageIndex{9}\). Chiasmata are essential for the attachment of homologous chromosomes to opposite spindle poles (bipolar attachment) and for their subsequent segregation to opposite poles during meiosis I.

Figure \(\PageIndex{9}\): Chiasmata Promote Monopolar Attachment of Sister Chromatids and Their Co-Segregations Towards the Proper Pole during Meiosis I. Image from Hirose, Y., et al (2011) PLoS Genet. 7(3):e1001329

Mechanism of Homologous Recombination

Meiotic recombination is a tightly regulated process that is triggered by the programmed induction of DNA double-strand breaks (DSBs). Once formed, the ends of the DSBs are nucleolytically processed to generate 3′ single-stranded DNA (ssDNA) tails. Meiotic recombination factors then engage these ssDNA tails to form a nucleoprotein ensemble capable of locating DNA homology in the homologous chromosome and mediating invasion of the homolog to form a DNA joint, known as a displacement loop (D-loop). The 3′ end of the invading strand is extended by DNA synthesis, followed by the pairing of the non-invading 3′ single-stranded tail with the displaced ssDNA strand in the enlarged D-loop (second-end capture). After DNA synthesis and DNA ligation, a double Holliday Junction (dHJ) intermediate is formed. Resolution of the dHJ intermediate can result in crossover recombinants that harbor a reciprocal exchange of the arms of the homologous chromosomes.

Genetic studies have revealed that meiotic DSBs arise via the action of a protein complex that includes Spo11, which is homologous to archaeal Topo VIA, the catalytic subunit of a type II topoisomerase. Indeed, studies in S. cerevisiae, S. pombe, and M. musculus have shown that Spo11 becomes covalently conjugated to the 5′ ends of DNA through a tyrosine residue that is proposed to be the catalytic center of topoisomerase activity. Thus, mutations in the putative catalytic tyrosine residue of Spo11 engender the same phenotype as Spo11 deletion in S. cerevisiae, S. pombe, A. thaliana, and M. musculus. These observations collectively suggest that Spo11 directly catalyzes double-strand break (DSB) formation to trigger meiotic recombination. Figure \(\PageIndex{10}\) provides an overview of this process.

Figure \(\PageIndex{10}\): Overview of meiosis and meiotic recombination.Yadav, V.K. and Bouuaert, C.C. (2021) Front. Cell Dev. Biol 9:642737

Panel (A) shows a schematic of the formation of haploid gametes from a diploid cell with a single pair of homologous chromosomes. DSB formation and recombination promote homolog pairing and lead to the exchange of chromosomal fragments (crossovers) during synapsis.

Panel (B) shows that meiotic recombination is initiated by Spo11-mediated DSB formation and leads to crossovers via a ZMM-dependent double Holliday Junction (dHJ) resolution pathway or to non-crossovers via synthesis-dependent strand annealing.

Panel (C) shows the relationships between meiotic recombination and higher-order chromosome structure. DSB formation occurs within the loop-axis structure. As recombination progresses, the SC polymerizes between the axes and is disassembled before chromosome segregation. Axis proteins Red1 (red ovals) and Hop1 (yellow ovals) are shown.

Panel (D)shows that in metaphase I, homologs are held together through chiasmata and sister chromatid cohesion. Image from:

Following break formation, Spo11 remains covalently attached to the 5′-strands at both DNA ends and is released by an endonucleolytic cleavage reaction mediated by MRX (Mre11, Rad50, and Xrs2) and Sae2, which liberates Spo11 attached to a short oligonucleotide (Fig. 25.3.7B). 5′-3′ exonucleases further resect the 5′-strands to produce long single-stranded tails, which are then coated with the ssDNA-binding protein, RPA. RPA is then replaced by recombinases Rad51 and Dmc1. These form a nucleoprotein filament and search for sequence similarity, preferentially located on the homologous chromosome, producing D-loop structures. Following DNA synthesis using the homolog as a repair template, the recombination structures experience one of two main outcomes (Fig. 25.3.7B). The invading strand can be ejected from the donor by helicases, thereby providing an opportunity for the DNA ends to reanneal. This process is referred to as synthesis-dependent strand annealing (SDSA). It produces non-crossovers, that is, products not associated with reciprocal exchanges of chromosome fragments, but rather with the local transfer of genetic information from the repair template to the broken molecule, known as gene conversion. Alternatively, recombination structures are stabilized by the “ZMM” family of proteins and channeled through a pathway that produces mostly crossovers. Here, both ends of the break engage the donor to form a double Holliday Junction intermediate, which is resolved via a crossover-specific pathway involving MutLγ and Exo1.

Every aspect of meiotic recombination is tied to the structural organization of the chromosomes (Fig. 25.3.7C). Early in the meiotic prophase, chromosomes organize as a series of DNA loops that are anchored along a nucleoprotein axis. DSB formation happens in the context of this loop-axis structure. As recombination progresses, polymerization of a proteinaceous structure called the synaptonemal complex (SC) initiates between the two axes and elongates along their entire length. Recombination proceeds within the SC, inside a nodule embedded between the axes. After recombination is completed, the SC disassembles and crossovers, now cytologically visible as chiasmata, provide physical connections between the homologs until their segregation at anaphase (Fig. 25.3.7D).

Summary

(Summary written by Claude, Sonnet 4.6, Anthropic)

Homologous recombination (HR) is a universally conserved mechanism for repairing double-strand breaks (DSBs) and generating genetic diversity during meiosis. Its conservation across all three domains of life and in both DNA and RNA viruses reflects its fundamental importance to genome integrity and inheritance.

DSB repair by homologous recombination proceeds through a defined sequence of molecular events. After a DSB occurs, 5′→3′ resection of both ends creates 3′ single-stranded overhangs that are initially coated by RPA. RPA is then displaced by recombinase proteins (Rad51 in mitotic cells, Dmc1 in meiotic cells) that form nucleoprotein filaments capable of searching for sequence homology and mediating strand invasion into an intact homologous duplex to form a displacement loop (D-loop). DNA synthesis from the invading 3′ end uses the intact duplex as a template. The subsequent fate of the D-loop determines the recombination outcome. In the SDSA pathway—predominant in somatic cells—the newly synthesized strand is ejected from the D-loop by helicases and reanneals with the second resected end, producing a noncrossover product that restores the original sequence. This pathway avoids the loss of heterozygosity that would accompany somatic crossovers. Alternatively, stabilization of the D-loop by ZMM proteins and capture of the second DSB end generate a double Holliday junction (dHJ) intermediate. Resolution of the dHJ by MutLγ and Exo1 produces crossover recombinants with reciprocal exchange of flanking sequences. Three additional DSB repair pathways operate with different homology requirements: NHEJ ligates break ends in a template-independent manner; MMEJ uses microhomologies flanking the break; and SSA requires extensive homology between the two resected ends on the same molecule.

Meiotic recombination follows the same fundamental HR mechanism but is deliberately programmed to generate crossovers that are essential for gamete formation. Before meiosis I, the conserved Spo11 topoisomerase-related protein catalyzes controlled DSB formation throughout the genome by forming a transient 5′-phosphotyrosyl covalent linkage with DNA—a mechanism homologous to type II topoisomerase chemistry. MRX/Sae2 endonucleolytic cleavage releases Spo11 attached to short oligonucleotides, and subsequent resection generates the 3′ ssDNA tails that recruit Rad51 and Dmc1 for strand invasion into the homologous chromosome rather than the sister chromatid.

The synaptonemal complex (SC), an evolutionarily conserved protein scaffold unique to meiotic prophase I, provides the structural framework that promotes interhomolog recombination and ensures each homolog pair receives at least one crossover. Assembly proceeds hierarchically: lateral elements (SYCP2, SYCP3) form along each chromosome axis during leptotene; transverse filaments (SYCP1) zip lateral elements of homologs together during zygotene; and the central element (SYCE1, SYCE2, SYCE3, TEX12) completes the tripartite structure during the fully synapsed pachytene stage. Recombination intermediates containing dHJs form within recombination nodules embedded in the central region of the SC, and their resolution produces crossovers that become cytologically visible as chiasmata as the SC disassembles at diplotene.

Chiasmata are not merely a record of recombination—they are mechanistically essential for accurate chromosome segregation. By providing physical connections between homologous chromosomes (together with sister chromatid cohesion), chiasmata enable bipolar attachment to the meiotic spindle and faithful co-segregation of homologs to opposite poles at meiosis I. The subsequent meiosis II division separates sister chromatids, ultimately producing four genetically unique haploid gametes. Two independent mechanisms ensure genetic diversity among gametes: random assortment of non-homologous chromosome pairs at meiosis I, and crossover recombination during meiotic prophase I. Together, these mechanisms continuously generate novel allelic combinations in offspring that are the raw material for natural selection and evolutionary adaptation—functions for which HR has been conserved since the earliest eukaryotes.

 

References

1. Hollingsworth, N.M (2020) A new role for the synaptonemal complex in the regulation of meiotic recombination. Genes and Dev. 34: 1562-1564. Available at: http://genesdev.cshlp.org/content/34/23-24/1562.full

2. Seo, E.K., Choi, J.Y., Jeong, J-H., Kim Y-G, Park, H.H. (2016) Crystal structure of C-terminal coiled-coil domain of XYCP1 reveals the non-canonical anti-parallel dimeric structure of transverse filament at the synaptonemal complex. PLOS one: DOI 10.1371. Available at: https://www.researchgate.net/publication/306394048_Crystal_Structure_of_C-Terminal_Coiled-Coil_Domain_of_SYCP1_Reveals_Non-Canonical_Anti-Parallel_Dimeric_Structure_of_Transverse_Filament_at_the_Synaptonemal_Complex

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6. Hirose, Y., Suzuki, R., Ohba, T., Hinohara, Y., Matsuhara, H., Yoshida, M., Itabashi, Y., Murakami, H., and Yamamoto, A. (2011) Chaismata Promote Monopolar Attachment of Sister Chromatids and Their Co-Segregation Toward the Proper Pole during Meiosis I. PLoS Genet. 7(3):e1001329. Available at: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1001329

7. Yeh, H-Y., Lin, S-W., Wu, Y-C., Chan, N-L., and Chi P. (2017) Functional Characterization of the Meiosis-Specific DNA Double-Strand Break Inducing Factor, SPO-11 from C. elegans. Scientific Reports 7:2370. Available at: https://www.nature.com/articles/s41598-017-02641-z#rightslink

8. Yadav, V.K., and Bouuaert, C.C. (2021) Mechanism and Control of Meiotic DNA Double-Strand Break Formation in S. cerevisiae. Front. Cell Dev. Biol. 9:642737. Available at: https://www.frontiersin.org/articles/10.3389/fcell.2021.642737/full