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Two proteins preserve vital genetic information

Understanding every aspect of cell division helps explain the origins of key genetic disorders, including cancers. Cancer is often driven by genetic mutations acquired over time to a person's DNA. Alterations can occur if proteins do not properly organize and separate as cells divide and multiply.


Now, research from The Wistar Institute shows how two key proteins organize chromosomes in our genome, and shed light on one of the key genetic processes going on in every one of us. With this information, scientists may be able to pinpoint cancers from their genetic mutations.

Their findings were published in the journal Nature Genetics.

"Understanding the three-dimensional structure of our genome is critical if we are to properly understand key functions like transcription, DNA replication and repair," said Ken-ichi Noma PhD, associate professor in the Gene Expression and Regulation program at Wistar and lead author of the study.


Each of our cells contains enough DNA that,
if stretched out in a line, would total
about six feet in length.


Condensin and cohesin are two key protein complexes that organize DNA in our chromosomes. Condensin helps compact genetic information into our cells and facilitates chromosome formation. Cohesin helps by regulating chromatids — the two strands along which a chromosome divides.

While researchers know the roles of condensin and cohesin, exactly how they organized chromosomes was unclear. Ken-ichi Noma has extensively studied the three-dimensional structure of our genomes. Using yeast, as it undergoes cell division very similar to humans, he and his colleagues were able to see that although condensin and cohesin bind to the exact same position on a chromosome, the chromatin complexes they handle vary by size.

Cohesin helps associations between chromatins located close to one another, between loci positioned within 100 kb of each other. Condensin, however, can make associations between chromatins ranging over greater distances. If either cohesin or condensin does not organize these gene components accurately, the consequences could be a host of diseases including cancers.


"How condensin is able to assemble the specific structure of mitotic chromosomes and how this organization promotes segregation during mitosis are two significant questions that have faced those of us working in genome biology."

Ken-ichi Noma PhD, Associate Professor, Gene Expression and Regulation program, Wistar Institute, Philadelphia, Pennsylvania, USA, and lead author.


Previously, Noma's lab had shown that many genes are connected to centromeres. Centromeres are sites where two chromatids — copies of newly replicated chromosomes — are positioned to be accurately split during mitosis. Condensin mediates the clustering of RNA polymerase III genes (abbreviated Pol III genes) and Pol II-transcribed "housekeeping" genes needed for every cell to function properly.

Studying yeast mitosis, the researchers identified a subunit of condensin called Cnd2 which binds to the TATA box-binding protein (TBP). TBP is a factor required in every type of transcription. When Cnd2 binds to TBP, it recruits condensin to stick onto Pol III genes and Pol II-transcribed housekeeping genes. Condensin then sticks these genes to the centromeres. When mitosis occurs, gene information is protected and intact and chromatins are split apart.


"The more we know about the role of condensin and cohesin, the more we learn about key processes in the cell cycle and how cancer can be controlled."

Ken-ichi Noma PhD


Abstract
It is becoming clear that structural-maintenance-of-chromosomes (SMC) complexes such as condensin and cohesin are involved in three-dimensional genome organization, yet their exact roles in functional organization remain unclear. We used chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) to comprehensively identify genome-wide associations mediated by condensin and cohesin in fission yeast. We found that although cohesin and condensin often bind to the same loci, they direct different association networks and generate small and larger chromatin domains, respectively. Cohesin mediates associations between loci positioned within 100 kb of each other; condensin can drive longer-range associations. Moreover, condensin, but not cohesin, connects cell cycle–regulated genes bound by mitotic transcription factors. This study describes the different functions of condensin and cohesin in genome organization and how specific transcription factors function in condensin loading, cell cycle–dependent genome organization and mitotic chromosome organization to support faithful chromosome segregation.

This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and the NIH Director's New Innovator Award Program of the National Institutes of Health under award DP2-OD004348. Support for shared resources used in this study was provided by Cancer Center Support Grant (CCSG) P30CA010815 to the Wistar Institute.

Co-authors of this study from The Wistar Institute include Kyoung-Dong Kim, Hideki Tanizawa, and Osamu Iwasaki.

About The Wistar Institute
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
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Aug 26, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Ace2 target sites form domain boundaries.
Image Credit: The Wistar Institute


 


 

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