Connell Lecture Series: Dr. Agata Smogorzewska

written by Kate Jiang

Dr. Agata Smogorzewska is an associate professor at the Rockefeller University. On December 8th, 2021, she gave a Connell lecture on her lab’s research in DNA interstrand crosslink repair and its link to tumorigenesis. I spoke with Dr. Smogorzewska to learn about the stories behind her research.

As a daughter of an immunologist and a physician, and surrounded by family members who are chemists, Dr. Smogorzewska thought part of her interest in science could have stemmed from the genes that ran in the family. Although she thought she would be a cellist when she played the cello in primary school, everything changed when she started learning—and became proficient at—biology in high school. “I just found mitosis fascinating. I thought it was the coolest thing on earth, and the fact that we didn’t really understand how this beautiful process happened was really interesting to me—and it made me realize that there are a lot of things that we don’t understand.”

When Dr. Smogorzewska went to the university, she worked in a few biology labs. The research experience made her realize that not only did she like biology, but she also wanted to combine it with the aspects of human disease and medicine. This led her to pursue a MD/PhD program and residency in clinical pathology to get the necessary medical training to conduct human studies. Getting back to the bench to do research, however, had been her goal from the start. “In medical school you realized that you can diagnose things, and some diseases have good responses [to] drugs and can be treated; but in reality, the knowledge is not at all complete—you have very limited understanding of the pathophysiology of how the diseases occur, and even less knowledge about how to treat them.” Dr. Smogorzewska described that, in a way, the Fanconi Anemia (FA) pathway—the DNA repair pathway named after the FA disease and is the main focus of her lab’s research—is a perfect example of how human genetics drive the understanding of mechanisms of DNA repair.

Interstrand crosslinks, or ICLs, are a form of DNA damage in which the opposite strands of DNA are covalently linked and cannot be bypassed by DNA polymerases. Cells utilize the FA pathway to repair these crosslinks, and deficiencies in FA pathway genes lead to the FA disorder characterized by developmental abnormalities, bone marrow failure, and predisposition to cancer. Dr. Smogorzewska’s interest in the FA pathway stemmed from her postdoctoral work in Dr. Stephen Elledge’s lab. From a proteomic screen where they uncovered several proteins that are phosphorylated upon DNA damage, she focused on KIAA1794, an unknown protein that resulted in a high sensitivity against an ICL-inducing chemical when depleted. Dr. Smogorzewska soon started to tackle the question of how KIAA1794 acts to promote the repair of ICLs.

During a visit to the Cold Spring Harbor Laboratory, where “there was nothing else to do at night”, she began to copy and paste fragments of the mysterious protein’s sequence and search them in different databases. She found a similarity between KIAA1794 and FANCD2, at the site where FANCD2 was known to be ubiquitinated—a feature that is essential for FANCD2’s repair function in the FA pathway. Suddenly everything became clear. With great excitement she immediately wrote up an outline of a paper that evening with all the required experiments listed out, including the prediction that the gene encoding for KIAA1794 would be mutated in patients with FA, and sent it to her mentor—despite not having any experimental evidence at all! Nevertheless, Dr. Smogorzewska and her colleagues eventually proved their model and published the story in 20071. The KIAA1794 protein was subsequently renamed to FANCI, and is known to play a key role in ICL repair today.

As a scientist, Dr. Smogorzewska enjoys discovering new things and trying to understand the unknowns. To her, the fun of research comes from doing detective work to solve science “puzzles”, and sometimes getting unexpected answers from that. One example is a story about proteosomal shuttling proteins that regulate genome integrity2. At first, even though cells without the shuttling proteins are clearly deficient in replication stress response, the substrates of these proteins could not be identified; making guesses and looking at potential candidates failed to reveal the answer as well. However, when they took an unbiased approach with a technique called iPOND (isolation of proteins on nascent DNA), which allowed for the identification of proteins that interact with newly-replicated DNA, the results were delightfully surprising. “You look at the list of proteins that show up as being enriched, and you almost fall off your chair because you realize that there’s a protein that’s definitely a candidate just based on the name of it,” said Dr. Smogorzewska. The protein was called RTFDC1, standing for Replication Termination Factor 2 Domain-Containing protein 1. “The fact that these words—replication termination—you’re just like, oh my God, that’s the protein you are looking for.” For Dr. Smogorzewska, getting answers to such long-standing questions is a gratifying experience.

In addition to the excitement of making new discoveries, Dr. Smogorzewska also enjoys interacting with other scientists, especially trainees. “Scientists who are just entering their training—students—[are] great because they are fearless, and I really like that.” As a parting thought, she advises students to be fearless when tackling science questions. “Find a question that interests you, answer the question. The other thing is to work hard to get to the answer. Sometimes it just takes a lot of work to get to where you are going to find the answer—and I think not being afraid of that is important.”

You can learn more about Dr. Smogorzewska’s research at http://smogorzewska-lab.org/.

Reference:

1. Smogorzewska, A., Matsuoka, S., Vinciguerra, P., McDonald, E. R., 3rd, Hurov, K. E., Luo, J., Ballif, B. A., Gygi, S. P., Hofmann, K., D’Andrea, A. D., & Elledge, S. J. (2007). Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell129(2), 289–301.

2. Kottemann, M. C., Conti, B. A., Lach, F. P., & Smogorzewska, A. (2018). Removal of RTF2 from Stalled Replisomes Promotes Maintenance of Genome Integrity. Molecular cell, 69(1), 24–35.e5.

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Correction: In the original blog post published on February 11th, 2022, the author referred to the discovery of KIAA1018/FAN1 (Smogorzewska et al. 2010, Molecular Cell), while the story was supposed to be about the discovery of KIAA1794/FANCI (Smogorzewska & Matsuoka et al. 2007, Cell). This blog post has since been updated with the correct information on February 15th, 2022. The author sincerely apologizes for the mistake and thanks Dr. Agata Smogorzewska for the correction and editing suggestions.



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