Clarke stands out with seminal
discoveries in protein methylation
and inspired teaching

Published April 01 2018

“It is such an honor to be named for this award emphasizing both science and mentorship. I am grateful to have had so many wonderful scientists in my laboratory and as collaborators. I hope I have learned well from my own mentors, including James E. ‘Skip’ Skinner, Neal Cornell, Guido Guidotti, Daniel E. Koshland Jr. and David Sigman.”

— Steven Clarke

Steven Clarke, distinguished professor of chemistry and biochemistry at the University of California, Los Angeles, has won the 2018 William C. Rose Award for illuminating how protein modifications by methyl groups regulate fundamental biological processes.

Christine Hrycyna, who earned her Ph.D. in Clarke’s lab and now heads the chemistry department at Purdue University, nominated him for the award, writing, “Not only has he sustained a highly impressive level of novel research in biochemistry and molecular biology over the past nearly forty years, but he has also been instrumental in mentoring and launching the careers of entire generations of scientists.”

One of many scientific insights emerging from Clarke’s laboratory is that protein damage repair is a fundamental cellular process and a response to aging. It is well appreciated that DNA undergoes damage and repair throughout an organism’s lifetime. However, prior to Clarke’s seminal work, it was less appreciated that damaged proteins can be recognized and repaired by specific enzymes.

Clarke and his student Philip McFadden discovered the first example of a protein repair methyltransferase in 1982. Two amino acid residues, asparaginyl and aspartyl, can react spontaneously with the protein backbone, leading to a kink in the protein that can render it nonfunctional. This kink (isoaspartyl residue) can be modified by a widely conserved methyltransferase, leading to regeneration of the normal aspartyl residue. The deletion of this repair methyltransferase affects the lifespan of organisms including worms, flies and mice, which indicates its fundamental role.

Subsequent work in the Clarke laboratory has pioneered bioinformatic approaches to find candidate methyltransferases from genomic data and uncovered their diverse roles of methylation reactions in biology. These include the protein phosphatase 2A C-terminal leucine methyltransferase, the ribosomal protein histidine methyltransferase and the N-terminal X-P-K methyltransferase. In addition, in collaboration with other laboratories, he and his students identified the C-terminal isoprenylcysteine methyltransferase and found the first protein arginine methyltransferase and additional members of its family. Finally, he and his students discovered small-molecule methyltransferases involved in the repair of age-damaged S-adenosylmethionine (a cosubstrate involved in methyl group transfers and other reactions), yeast invasive growth, and resistance to the cantharadin toxin produced by blister beetles.

David Eisenberg, professor of molecular biology at UCLA, wrote in support of the nomination of Clarke’s “sustained, highly original contributions to biochemical and molecular biological research,” and Jamil Momand, a professor of biochemistry at California State University, Los Angeles, wrote, “At the research level … Steve is head and shoulders over the majority of independent scientists. He is a pioneer in the areas of aging and protein processing; and in the field of protein methylation, he is the top expert.”

The Rose Award also recognizes outstanding commitment to scientific education. Clarke has published 290 papers during his 39 years at UCLA, the majority of which have his graduate and undergraduate students as first authors. Forty-seven graduate students have completed their Ph.D. with Clarke and have gone on to become professors and scientists in industry and academia as well as to have careers in law and finance. Another aspect of Clarke’s scientific education legacy is his work since 1988 as the director of the National Institutes of Health-funded UCLA Cellular and Molecular Biology Training Program, where he has developed research integrity training and worked to increase the diversity of Ph.D. candidates.

Zhaohui Sunny Zhou, a professor of chemistry and chemical biology at Northeastern University, wrote that Clarke is defined by his attitude of collaboration and dedication as a mentor. “Because of Steve’s model as a generous leader,” Zhou wrote, “the whole field has been much more collaborative, and as a result, more productive.” And Mary Beth Mudgett, professor of biology at Stanford University, wrote, “An impactful scholar like Steve never stops mentoring. He is forever inspirational!”

Harvey Herschman, a distinguished research professor at the David Geffen School of Medicine at UCLA, wrote that Clarke’s seminars are “always engaging, informative, well organized, delivered with astonishing enthusiasm, inspiring, and — above all — clear.” Clarke’s lecturing can be experienced on the UCLA YouTube channel or live at the American Society for Biochemistry and Molecular Biology award ceremony.

Clarke will receive his award during the 2018 ASBMB Annual Meeting in San Diego, where he will deliver an award lecture titled “What can protein methylation tell us about biology? Histones, ribosomes, translation factors and cancer.” The presentation will take place at 8:30 a.m. April 25 in Room 6C of the San Diego Convention Center.

Nathalie Gerassimov Nathalie Gerassimov is a Ph.D. student at Johns Hopkins School of Medicine.