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$2.8M award to help unravel mysteries of disease-causing DNA folding errors

IU researchers will explore ‘folding mechanisms’ implicated in certain genetic disorders and cancers under grant from NIH

For Immediate Release Jan 16, 2024

BLOOMINGTON, Ind. — An Indiana University biologist has been awarded $2.8 million from the National Institutes of Health’s National Institute of General Medical Sciences to investigate the DNA folding machinery inside cells. DNA folding errors can cause a wide variety of diseases, including genetic disorders and certain types of cancer.

Stephen Bell. Photo by Chris Meyer, Indiana University Stephen Bell. Photo by Chris Meyer, Indiana University

Every human cell contains about 2 meters of DNA, said grant recipient Stephen Bell, an IU Distinguished Professor of biology and molecular and cellular biochemistry in the College of Arts and Sciences at IU Bloomington . The proteins under investigation — called structural maintenance of chromosome, or SMC, proteins — assist in compressing DNA into structures less than 10 millionths of a meter in length, through folding. These structures are chromosomes.

DNA misfolding has been linked to a variety of genetic diseases, such as wound healing disorders and Cornelia de Lange syndrome, whose symptoms include malformed arms and hands, cognitive issues, seizures and microcephaly. Misfolded genes have also been shown to play a role in some cancers.

“There has been a lot of research on gene expression, and we know a lot about how DNA replicates — how it splits apart and is rebuilt,” Bell said. “What isn’t as well understood are the systems that organize DNA, including the DNA compaction system, and these are of fundamental importance to chromosomal health. Technology has advanced enough that we finally have the tools to study these processes biochemically.”

To conduct their research, Bell and colleagues will use Sulfolobus, a genus of archaea that serves as a model species for human DNA. (Bell’s previous research has shown that these single-celled organisms share key similarities with human cells.) Along with bacteria and eukaryotes, archaea comprise one of the three domains of life on Earth.

The similarity to human cells is significant since Sulfolobus, which grow in harsh environments such as hot springs or volcanos, contain heat-stable enzymes. This makes these “boiling acid bugs” an ideal research species because the high stability of their cellular machinery aids in their purification and analysis, Bell said.

Notably, he added, one of the most significant biological research tools of the 20th century — polymerase chain reaction, or PCR, which allows medical researchers and scientists to amplify small pieces of DNA for genetic testing — was enabled through research on another temperature-resistant species, Thermus aquaticus. These bacteria were first identified by the late Thomas Brock, who was a faculty member at IU at the time of their discovery.

In addition, Bell said microorganisms such as archaea offer significant research advantages over more complex lifeforms because their cellular machinery is simpler than humans’, but the fundamental principles are the same.

“If you wanted to understand an internal combustion engine, you could study a Model T or you could study a Ferrari; each operates on the same fundamental parameters,” Bell said. “But it’s much easier to study the more basic structure; it’s easier to strip apart the machinery.”

The tangled structure of a protein shown in purple and pink The structure of Alba, one of the key DNA-organizing proteins in archaea, was determined through a collaboration between Bell's lab at IU Bloomington and the lab of Malcolm White at the University of St. Andrews in Scotland. Image courtesy of Stephen Bell and Malcolm WhiteUnder the NIH grant, Bell said his lab will deconstruct the Sulfolobus SMC mechanism, after which they plan to develop an artificial version — a field of science known as “synthetic biology.” Building their own version of the DNA compaction system will allow the researchers to better control and manipulate it for study, he said.

“After we rebuild it, we’ll want to create an even simpler model,” Bell added. “The goal is always to reduce the potential number of potentially conflicting variables. Once we’ve stripped everything else away, we can really start to grasp how it all works.”

Also advancing this goal is an unexpected new discovery on SMC proteins from Bell’s lab, published Dec. 18 in the journal Nature Microbiology. In the study, Bell and Catherine Badel, a postdoctoral researcher at IU at the time of the study, reported that another form of archaea known as Aeropyrum pernix does not contain SMC proteins, despite their key role in organizing DNA in all other living organisms studied to date.

“When we discovered that Aeropyrum lacked SMC proteins, we were shocked,” he said. “How they’re alive is a mystery. What we’ve found is that their gene expression itself seems to drive some sort of simplified chromosomal organization.”

Aeropyrum are in the same phylum as Sulfolobus, the model species that shares key similarities to human cells, so unraveling the mystery of Aeropyrum’s survival without SMC proteins could offer another key to understanding the SMC function in other archaea, he said. It could also shed new light on more complex cells, including human cells.

“What we learn could illuminate important evolutionary transitions between an ancient mode of chromosome organization and that which is utilized in more complex cells,” he said. “This part of the project is mostly driven by curiosity, but a lot of notable research started out with simple questions like ’How?’ or ’Why?’”

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