Two UW biochemists seek to unlock secrets with NIH New Innovator Awards

With the support of the National Institutes of Health 2022 High Risk, High Reward New Innovator Awards, University of Wisconsin-Madison biochemistry professors Ci Ji Lim and Amy Weeks are pursuing some of their more unconventional ideas about repeating DNA sequences and how cells rearrange proteins as they receive signals from outside their walls.

More than half of the human genome is made up of repetitive DNA sequences. Lim studies telomeres, repeating DNA sequences that appear at the ends of chromosomes, including how telomeres are maintained and organized and how they replicate.

Research to date has mainly focused on the length of these repeat sequences – shorter telomeres have been associated with aging, while both shorter and longer telomeres have been linked to certain cancers. But Lim hopes to change that.

Ci Ji Lim

According to Lim, the research suggests that telomere length is just one variable that scientists could consider in their quest to understand health, disease, and basic biological functions related to telomeres. How certain proteins bind along this repetitive DNA sequence could have important implications that scientists don’t yet understand.

“It’s time we got a sense of what the distribution of proteins is like along repetitive DNA sequences and how that changes with different telomere states.” Right now it’s a black box, Lim says. “The tools that we are going to develop, with others, could overcome this barrier and allow us to understand this system, bringing into synergy an entire field of research in chromosomal biology on repetitive genomic sequences.

Using gene-editing tools and advanced DNA sequencers, Lim plans to study the arrangement of proteins along telomeres to understand if their location and order matter.

“I think this work could provide the missing link between previous studies that use oversimplified telomere systems and the complex protein-DNA interactions that occur at the telomere level in cells,” Lim says.

Weeks’ research group draws on a variety of disciplines including protein engineering, chemical biology, cell biology and proteomics – the study of large sets of interrelated proteins – using a multitude of tools and technologies different, to map protein dynamics in humans and how these proteins respond in time and space to signals from outside cells.

Amy Weeks

A subset of his research involves deciphering the biological functions of post-translational modifications, that is, the chemical changes that reprogram the organization of cells after the production of a protein. These changes occur on a continuum of time scales, ranging from seconds to days depending on the biological signals involved.

There are hundreds of thousands of post-translational modifications, but scientists only know the functions of a few thousand. Weeks plans to develop automated tools that can be applied to all proteins in humans and will allow scientists to develop targeted hypotheses about what different post-translational modifications do.

“I think you’ll hear some people in the field of cell signaling say that many post-translational modifications are just spectators, that they don’t have an important function. I don’t think that’s true,” Weeks says. “I think it’s analogous to when the human genome was first sequenced. People used to say that 90% of the human genome was junk DNA, and now we know that that’s not true. I think something similar is true of these protein modifications.

Once developed, Weeks’ tools could help scientists understand how proteins move between cell compartments in response to signals they receive and how this relates to function.

Grants to Lim and Weeks are among 71 researchers who received New Innovator awards this year. The fellowships, created to support unconventional approaches to key challenges in biomedical and behavioral research, provide up to $1.5 million over three years for exceptionally innovative research by early career researchers.

Learn more about the New Innovator Awards on the NIH website.

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