Current Research

Abby Dernburg researches the molecular mechanisms underlying chromosome organization and dynamics during meiosis, the special cell cycle that enables sexual reproduction. Her group uses diverse experimental approaches, including genetic analysis, high-resolution and real-time imaging, biochemistry, and structural biology. Their long-term goal is to understand how chromosomes segregate faithfully during meiosis, and specifically how the processes of homologous pairing, synapsis, and recombination are executed during meiotic prophase.

Meiotic Chromosome Pairing and Synapsis
All sexually reproducing organisms rely on meiosis, the specialized chromosome segregation process by which a diploid cell partitions its genetic information into haploid cells, which become sperm, eggs, pollen, or spores. The defining feature of meiosis is that the two homologous copies of each chromosome contributed by the two parents must separate from each other. To accomplish this "reductional" segregation, homologous chromosomes first pair with each other and undergo crossover recombination, events that occur during meiotic prophase. Errors in this process give rise to aneuploidy, infertility, and in some cases to trisomies that cause developmental disorders such as Down syndrome and Klinefelter syndrome.

My lab is studying chromosome dynamics during this unique cell cycle. We investigate how the architecture of meiotic chromosomes is established and how it contributes to homolog pairing, how the synaptonemal complex is built and regulated, how pairing and synapsis are intertwined with meiotic recombination, and how regulatory circuits ensure that these processes occur in a coordinated fashion to enable accurate transmission of genetic information from one generation to the next. Most of our work uses the model organism Caenorhabditis elegans, a small, free-living roundworm (nematode) that offers many experimental advantages.

Chromosome Regions That Mediate Pairing and Synapsis Are Regulatory Hubs
Genetic studies in C. elegans have revealed that a special region near the end of each chromosome, known as the homolog recognition region or pairing center, is important for the pairing and segregation behavior of chromosomes during meiosis. Work in my lab has been unraveling the molecular activities that define these pairing centers. Having demonstrated that chromosomes lacking their pairing centers usually fail to pair and synapse with their partners, we identified a family of zinc finger (ZnF) proteins that bind to specific pairing centers and mediate their roles in pairing and synapsis. These proteins, known as HIM-8, ZIM-1, ZIM-2, and ZIM-3, mediate interactions between chromosomes and the microtubule cytoskeleton through a LINC (linker of nucleoskeleton and cytoskeleton) complex that spans the nuclear envelope. Molecular analysis of these linkages revealed that pairing centers represent an evolutionary variation on a widely conserved feature of meiosis: in most eukaryotes, the chromosome ends (telomeres) mediate similar links to the microtubule cytoskeleton during meiotic prophase. These cytoskeletal connections produce strong mechanical forces along microtubules, which lead to dramatic chromosome motions. Although the chromosome-associated proteins required for these connections have diverged, often beyond recognition, key nuclear membrane proteins and motors involved in meiotic chromosome movements are shared among most eukaryotes. We have found that these mechanical forces contribute to pairing and synapsis in several ways: they expedite the homology search process, they promote chromosome elongation and lengthwise alignment, and in C. elegans they are essential to trigger formation of the synaptonemal complex, the mysterious "glue" that holds homologs together throughout much of meiotic prophase and regulates meiotic recombination.

Our recent work has illuminated a regulatory cascade that acts at pairing centers to set meiotic chromosomes into motion. CHK-2, a kinase required for homolog pairing, synapsis, and recombination, modifies the ZnF proteins at pairing centers upon meiotic entry. By phosphorylating these proteins, CHK-2 enables them to recruit a Polo-like kinase, PLK-2, which is in turn required for pairing and synapsis. Concentration of PLK-2 at pairing centers, and its sequestration away from other chromosome regions, are important for regulating synapsis. Ongoing efforts are identifying the key substrates of CHK-2 and PLK-2, which we know to include both essential chromosomal proteins and components of the synaptonemal complex. Thus, these studies are revealing how chromosome architecture and dynamics are regulated during meiotic prophase and how this regulation promotes faithful execution of pairing, synapsis, and recombination.

Feedback Regulation of the Meiotic Cell Cycle
Work in my lab and many others has revealed the activities of checkpoints that can alter or abort the meiotic cell cycle in response to defects in chromosome pairing, synapsis, or recombination. We have recently found that failures in synapsis or crossover formation feed back to prolong the early stage of meiotic prophase by maintaining the activity of the CHK-2 kinase. We also discovered that these meiotic feedback mechanisms operate autonomously in each cell and influence the genome-wide pattern of double-strand break formation and crossover placement. However, how such meiotic errors are detected, and how this information is transduced to affect cell cycle progression, are still open questions.

Meiotic surveillance mechanisms depend on a family of conserved, meiosis-specific proteins that form part of the "axis" structure unique to meiotic chromosomes. These proteins contain HORMA domains, shared by several other proteins that act in diverse cellular processes. The HORMA domain was first characterized structurally through studies of the spindle assembly checkpoint protein Mad2, which revealed it to adopt a peptide-binding fold. Using a combination of biochemical reconstitution, crystallography (in collaboration with the laboratory of Kevin Corbett [Ludwig Institute for Cancer Research, University of California, San Diego]), and targeted mutations, we have recently determined that the four meiotic HORMA proteins in C. elegans are targeted to meiotic chromosomes through hierarchical binding of their HORMA domains to peptides in each others' C-terminal tails. Similar interactions occur between the two mammalian meiotic HORMA proteins. This knowledge has enabled us to manipulate the association of specific HORMA proteins with chromosomes, thereby shedding light on the quality control mechanisms that coordinate meiotic events, as well as on the essential roles of meiotic HORMA proteins in pairing, synapsis, and recombination.

Evolution of Meiotic Mechanisms
Meiosis arose once during evolutionary history, and many aspects of this process are widely conserved among sexually reproducing organisms. However, experimental studies in various species have also revealed surprising diversity in meiotic mechanisms. For example, in many organisms, early steps in recombination are required for chromosomes to pair and synapse with their homologs; yet in some metazoan species, pairing and synapsis occur normally even when the initial step in recombination is blocked (e.g., by mutation of the conserved enzyme that makes programmed DNA double-strand breaks during meiosis). Both C. elegans and the fruit fly Drosophila melanogaster are among such exceptions. We interpret these findings to indicate that (1) mechanisms other than recombination enable recognition between homologous chromosomes, and (2) in some organisms, these mechanisms have become robust enough that recombination is no longer required for pairing. Thus, C. elegans offers an opportunity to uncover these mysterious pairing mechanisms, and we are exploring this long-standing mystery through several independent approaches.

Emergence of recombination-independent homolog-pairing mechanisms in both C. elegans and Drosophila has been accompanied by loss of the gene encoding Dmc1. This meiosis-specific paralog of the Rad51 recombinase protein is required for meiotic chromosome pairing, synapsis, and recombination in most eukaryotes. Whole-genome sequence information has recently revealed that loss of Dmc1, as well as its cofactors Hop2 and Mnd1, has occurred independently in several roundworm lineages. Intriguingly, we noticed that the nematode Pristionchus pacificus, which has been developed as a satellite model organism, has intact copies of all three genes. The genomes of C. elegans and P. pacificus are remarkably similar, despite hundreds of thousands of years of divergence. At least superficially, the progression of meiosis in these two species also appears to be very similar. We have investigated the mechanism of homolog pairing in P. pacificus by engineering knockout alleles of dmc-1 and spo-11. Analysis of these mutants has revealed that, indeed, double-strand breaks and DMC-1 are required for pairing and synapsis, and that P. pacificus thus shares some central features of meiosis with other eukaryotes, which have diverged in the Caenorhabditids. We have also uncovered differences in the regulation of meiotic recombination between the two nematode species that give rise to higher crossover frequencies in P. pacificus. Future exploration of the diversity of meiotic mechanisms among nematodes offers a framework to understand the evolution of cell cycle progression and chromosome dynamics.

Grants from the National Institute of General Medical Sciences, the National Human Genome Research Institute, and the American Cancer Society have also supported recent work in the Dernburg lab. 

As of December 17, 2014

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