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Molecular & Cellular Biology

Chromosome Mechanics Guide Nuclear Assembly

Every one of our cells stores its genome within the nucleus – the quintessential subcellular structure that distinguishes eukaryotic cells from bacteria. When animal cells divide, they disassemble their nucleus, releasing individual chromosomes for proper segregation to daughter cells. At the end of cell division, the daughter cells reassemble a single nucleus around a complete set of chromosomes. The formation of a single nucleus is critical for the maintenance of genomic integrity. Individual chromosomes packaged into separate, small nuclei are prone to massive DNA damage, leading to mutations as well as chromosome rearrangement and loss. Cancer cells often contain small, multiple nuclei, which may drive genome disruption as well as disease progression. Nonetheless, how cells package their genome into just one nucleus has been a mystery.

A genetic screen for micronuclei

The Gerlich lab at the IMBA set out to solve this problem by screening for genes that are required to assemble a single nucleus in human cells. They uncovered “barrier-to-autointegration factor” (BAF), a multifunctional protein that binds DNA as well as many proteins. Without BAF, cells formed fragmented nuclei at the end of cell division. BAF was already known to link DNA to specific proteins at the nuclear membrane. Unexpectedly, Gerlich’s lab discovered that nuclear assembly did not require BAF’s association with nuclear membrane proteins. Instead, they found that BAF’s ability to bind and bridge distant DNA sites was essential to shape a single nucleus. 

A dense BAF-DNA network shapes a single nucleus

How does BAF’s association with DNA regulate formation of the nucleus? The authors found that BAF forms a compact and mechanically stiff network with DNA. This created a coherent surface mesh around the set of chromosomes, which is impenetrable for nuclear membranes. This barrier prevents membranes from separately enwrapping individual chromosomes, and therefore guides the formation of a single nucleus.

The work, published in the current issue of Cell, answers a fundamental question in biology and reveals an entirely unanticipated function for BAF. “Our findings suggest an entirely new role for DNA cross-bridging beyond genomic functions such as regulating gene expression and recombination, by forming boundaries and mechanical scaffolds of subcellular compartments. We are excited to further uncover the molecular mechanisms that shape mitotic chromosomes and control their interactions with other cellular components” says Gerlich.

Originalpublikation: „DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes”, Samwer et al. Cell doi.org/10.1016/j.cell.2017.07.038

 

About IMBA
IMBA - Institute of Molecular Biotechnology is one of the leading biomedical research institutes in Europe focusing on cutting-edge functional genomics and stem cell technologies. IMBA is located at the Vienna Biocenter, the vibrant cluster of universities, research institutes and biotech companies in Austria. IMBA is a basic research institute of the Austrian Academy of Sciences, the leading national sponsor of non-university academic research. www.imba.oeaw.ac.at

About the Vienna BioCenter
The Vienna BioCenter (VBC) is a leading life sciences location in Europe, offering an extraordinary combination of research, education and business on a single campus. About 1,700 employees, more than 1,300 students, 86 research groups, 17 biotech companies, and scientists from more than 40 nations create a highly dynamic environment. www.viennabiocenter.org

Timelapse visualizing BAF

BAF cross-bridges anaphase chromosomes prior to enwrapment in nuclear envelope
Immediately prior to enwrapment in nuclear envelope, BAF binds to the anaphase chromosome ensemble surface and induces millions of cross-bridges between neighboring DNA strands This ultimately connects the chromosomes into a stable ensemble, which is important for guiding the nuclear envelope membrane around all chromosomes and for the formation of a single nucleus from a set of independent chromosomes.

BAF forms a physical barrier at the chromatin surface
Purified chromatin was incubated with BAF, which results in the formation of a BAF-DNA network at the chromatin surface. This network can be visualized by the addition of defined macromolecules (a 500 kDalton dextran in this case) to the buffer solution. 60 seconds after the addition, the dextran has deeply penetrated the control chromatin, while the BAF-DNA network has largely prevented this. In human cells, this network prevents enwrapping of individual chromosomes and instead guides the nuclear envelope around all chromosomes.