Professor, Molecular Biology and Genetics
Interim Director, Weill Institute of Cell and Molecular Biology
Marcus Smolka is a Professor in the Department of Molecular Biology and Genetics, and a member of the Weill Institute for Cell and Molecular Biology. He received a Ph. D. in Brazil, at the State University of Campinas, and worked as a FAPESP fellow at the Institute for Systems Biology (Seattle, WA). In 2003, Dr. Smolka moved to San Diego, CA, for a post-doctorate at the Ludwig Institute for Cancer Research. He joined Cornell in 2008.
Smolka pioneered the use of mass spectrometry for the study of kinase substrates and mapping of phosphorylation signaling networks. With grants and awards from the NIH, ACS, Emerson Collective and various Cornell Initiatives, his lab has been applying proteomic approaches, in combination with genetics and biochemistry, to investigate fundamental mechanisms of genome maintenance, and their connections to cancer and reproductive biology. The Smolka Lab mapped the action of DNA damage signaling kinases in yeast and mammals, leading to the understanding of the mechanisms by which kinases control DNA repair, checkpoints, cell cycle and transcription. As a Research Scholar for the American Cancer Society, Smolka uncovered novel mechanisms for deactivation of DNA damage checkpoint signaling kinases, establishing novel paradigms for signaling regulation. Current work in the Smolka Lab continues to expand the network of DNA damage signaling in the context of cancer biology and meiosis. Smolka also engages in a range of collaborative efforts using quantitative proteomics to elucidate fundamental molecular mechanisms underlying metabolic control, cell polarity, protein trafficking, neurodegenerative diseases and bacteria-host interactions.
Cell Signaling and Genome Maintenance: Damage to our genetic material is a threat to our survival and a driving force of many diseases. Our fundamental research interest is in the mechanisms of genome maintenance and we focus on the key roles of DNA damage checkpoint kinases (ATR, ATM, CHK1 and CHK2). We are using mass spectrometry technologies, in combination with genetic and biochemical approaches, to study the organization, dynamics and regulation of DNA damage signaling in yeast and humans.
DNA Replication Stress: We are particularly interested in understanding how cells respond to DNA replication stress, a major endogenous source of DNA damage that drives cancer progression. In addition to its role in causing cancer, replication stress is also used to cure cancer. For example, numerous anti-cancer agents such as topoisomerase inhibitors, DNA crosslinkers and DNA alkylators, kill cancer cells by impairing the regulated progression of the replication machinery and inducing replication stress. Despite the importance of this topic, the molecular circuitry that allows cells to respond to and resist replication stress is far from understood. We are particularly interested in understanding how checkpoint kinases function in response to replication stress, with the overall goal of elucidating the fundamental mechanisms of genome maintenance during DNA replication.
Phosphoproteomics: Reversible protein phosphorylation is widely used by cells as a signaling mechanism. Understanding the molecular basis of kinase action and function requires knowledge of the kinase substrates, as well as comprehensive characterization of the dynamics and role of the phosphorylation events. Because many kinases are active in a cell and thousands of proteins are phosphorylated, the study of phosphorylation-mediated signaling pathways is challenging and powerful technologies are needed. We have developed and applied quantitative mass spectrometry technologies for the phosphorylation analysis of protein complexes and for global screens of in vivo kinase substrates. We are now expanding the use of these technologies to quantitatively characterize signaling dynamics and regulation at a proteome-wide scale.
- Molecular Cell (2021) - Checkpoint-mediated DNA polymerase ε exonuclease activity curbing counteracts resection-driven fork collapse.
- EMBO Journal (2021) - Phosphoproteomics reveals a distinctive Mec1/ATR signaling response upon DNA end hyper‐resection.
- EMBO Reports (2021) - In-depth and 3‐dimensional exploration of the budding yeast phosphoproteome.
- Nucleic Acids Research - Cancer (2020) - Intrinsic ATR signaling shapes DNA end resection and suppresses toxic DNA-PKcs signaling.
- Annual Review of Biochemistry (2020) - Checkpoint Responses to DNA Double-Strand Breaks.
- EMBO Journal (2019) - DNA damage kinase signaling: checkpoint and repair at 30 years.
- Genes & Development (2018) - Separable roles for Mec1/ATR in genome maintenance, DNA replication, and checkpoint signaling.
- Nucleic Acids Research (2018) - ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells.
- J Cell Bio (2017) - TOPBP1/Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1/Rad9.
- J Cell Biol (2016) - TOPBP1 takes RADical command in recombinational DNA repair.
- Mol Cell (2015) - Phosphoproteomics Reveals Distinct Modes of Mec1/ATR Signaling during DNA Replication.
- EMBO Journal (2015) - Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions.
- Nature (2013) - DNA Repair Scaffolds Dampen Checkpoint Signaling by Counteracting the Rad9 Adaptor. Patrice Ohouo, Yi Liu, Francisco M Bastos de Oliveira and Chu Jian "Frank" Ma and Marcus Smolka.
State University of Campinas - 2002
- Master of Science
State University of Campinas - 1999
- Bachelor of Science
State University of Campinas - 1996
Mass spectrometry, proteomics
Awards & Honors
- Research Scholar Award (2015) American Cancer Society
- BIOMG 8369: Foundations and Frontiers in Cellular and Molecular Biology - I
- BIOG 4990: Independent Undergraduate Research in Biology
339 Weill Hall
Ithaca, NY 14853
mbs266 [at] cornell.edu
Biochemistry, Molecular and Cell Biology
Genetics and Development
Marcus in the news
Jumana Badar, a fifth-year doctoral candidate in the graduate field of biochemistry, molecular and cell biology, has been selected for the 2023 Harry and Samuel Mann Outstanding Graduate Student Award.
- Molecular Biology and Genetics
Researchers have uncovered a novel pathway that explains how cancer cells become resistant to chemotherapies, which in turn offers a potential solution for preventing chemo-resistance.
- Molecular Biology and Genetics
- Health + Nutrition