Welcome to the Smolka Lab!


We study mechanisms of genome maintenance with a focus on DNA lesion detection and signaling. Our lab uses mass spectrometry technologies, in combination with genetic and biochemical approaches, to elucidate the organization, dynamics and regulation of DNA damage signaling in yeast and mammals.

The integrity of our genome is especially at risk while it is being replicated. During DNA replication, the DNA must be “unzipped”, giving rise to structures known as replication forks. While traversing the genome, replication forks often encounter obstacles to their progression, including DNA lesions, hard-to-replicate sequences, transcription intermediates, or protein-DNA complexes. These encounters are potential sources of DNA breaks, chromosomal rearrangements and aneuploidy, all of which are hallmarks and drivers of cancer. Proper control of replication fork progression is therefore essential for genome integrity and cancer avoidance. Paradoxically, 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. Our laboratory studies how cells sense, signal and prevent DNA replication stress to ensure faithful genome replication. We seek a deep mechanistic and integrated understanding of the replicative stress response and its implications for tumorigenesis and improved cancer treatment.fork

A phosphorylation code for the control of the replication stress response. We are investigating how the actions of kinases are translated into a coordinated cellular response that ensures proper completion of genome replication. As shown in the figure below, our recent work using budding yeast as a model organism has uncovered how phosphorylation events mediated by CDK and checkpoint kinases form a “code” of combinatorial protein interactions that lead to distinct functional outputs, therefore allowing timely coordination of DNA replication, cell cycle and DNA repair (1-3). Central to this combinatorial mode of regulation is the multi-BRCT domain scaffold Dpb11, capable of “reading” a range of phosphorylation events and physically coupling distinct protein complexes. We are currently investigating how TOPBP1, the human ortholog of Dpb11, coordinates DNA damage responses via a similar phosphorylation-mediated code.


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 (4). We are now expanding the use of these technologies to quantitatively characterize signaling dynamics and regulation at a proteome-wide scale.



1. Cussiol, J.R., et al. EMBO J 34, 1704-17 (2015).

2. Ohouo, P.Y. et al. Nature 493, 120-4 (2013).

3. Ohouo, P.Y. et al. Mol Cell 39, 300-6 (2010).

4. Bastos-de-Oliveira, F., Kim, D.  et al. Mol Cell 57, 1-9 (2015).


We are grateful for the funding provided by:










Marcus Smolka, PhD

Marcus Smolka is an Associate 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 visiting fellow with Dr. Ruedi Aebersold, 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, working with DNA damage checkpoint kinases and phosphoproteomics in the laboratory of Dr. Huilin Zhou. He joined Cornell in 2008.

Marcus B. Smolka, Ph.D
Weill Institute for Cell and Molecular Biology
Department of Molecular Biology and Genetics
Cornell University
339 Weill Hall
Ithaca, NY 14853-7202


(607)255-0274 (Office)
(607)255-0174 (Lab)

Selected Publications

J Cell Bio (2017) - TOPBP1/Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1/Rad9.. Yi Liu, José Renato Cussiol, Jennie Rae Sims, …, Marcus Bustamante Smolka.
Commentary by the Gasser Lab: A game of musical chairs: Pro- and anti-resection factors compete for TOPBP1 binding after DNA damage.

Chromosoma (2016) - Slx4 scaffolding in homologous recombination and checkpoint control: lessons from yeast. Jose Cussiol, Diego Dibitetto, Achille Pellicioli, and Marcus Smolka. [Epub ahead of print] Review.

J Cell Biol (2016) - TOPBP1 takes RADical command in recombinational DNA repair. Yi Liu and Marcus Smolka.

Mol Cell (2015) - Phosphoproteomics Reveals Distinct Modes of Mec1/ATR Signaling during DNA Replication. Francisco Bastos de Oliveira, Dongsung Kim, José Renato Cussiol, Jishnu Das, Min Cheol Jeong, Lillian Doerfler, Kristina Hildegard Schmidt, Haiyuan Yu, Marcus Smolka.

EMBO Journal (2015) - Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions. José R Cussiol, Carolyn M Jablonowski, Askar Yimit, Grant W Brown, Marcus B Smolka

EMBO Journal (2015) - Assembly of Slx4 signaling complexes behind DNA replication forks. Attila Balint, TaeHyung Kim, David Gallo, Jose Renato Cussiol, Francisco Bastos de Oliveira, Askar Yimit, Jiongwen Ou, Ryuichiro Nakato, Alexey Gurevich, Katsuhiko Shirahige, Marcus Smolka, Zhaolei Zhang, Grant Brown

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.

J Biol Chem.(2013) - Interactome analysis reveals ezrin can adopt multiple conformational states. Raghuvir Viswanatha, Jessica Wayt, Patrice Ohouo, Marcus Smolka, Anthony Bretscher.

Cell Cycle (2012) - The many roads to checkpoint activation. Patrice Ohouo and Marcus Smolka.

J Cell Biol (2012) - Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells. Raghuvir Viswanatha, Patrice Ohouo, Marcus Smolka, and Anthony Bretscher.

Cell Cycle (2012) - The checkpoint transcriptional response: Make sure to turn it off once you are satisfied. Marcus Smolka, Francisco Bastos de Oliveira, Michael Harris, and Robertus A M de Bruin.

EMBO Journal (2012) - Linking DNA replication checkpoint to MBF cell-cycle transcription reveals a distinct class of G1/S genes. Francisco Bastos de Oliveira, Michael Harris, Pijus Brazauskas, Robertus A M de Bruin and Marcus Smolka.

EMBO Journal (2012) - DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1. Anna Travesa, Dwight Kuo, Robertus AM de Bruin, Tatyana I Kalashnikova, Marisela Guaderrama, Kevin Thai, Aaron Aslanian, Marcus Smolka, John R Yates III, Trey Ideker and Curt Wittenberg.

Cell (2011) - TORC1 regulates endocytosis via Npr1-mediated phosphoinhibition of a ubiquitin ligase adaptor. JA MacGurn, PC Hsu, Marcus Smolka and Scott Emr. 147(5):1104-17.

Cell Cycle (2011) - A touching moment for Smc5/6: from ssDNA binding to repair. Patrice Ohouo, Marcus Smolka, (April 2011) (comment on Roy MA, et al. Cell Cycle).

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