Welcome!
We study regulatory signaling networks involved in the maintenance and replication of eukaryotic genomes. We employ proteomic technologies, in combination with genetic, cell biological and biochemical approaches, to elucidate the organization, dynamics and regulation of DNA damage signaling in yeast and various mammalian systems. 

 

Postdoc positions available. Please send CV to email.

 

Lab News:

(To learn more about our research projects, please scroll further down)
  • August 2024: New JBC paper by graduate student Shannon Marshall and postdoc Marcos Navarro uncovers new features of DNA-PKcs kinase specificity. 
  • August 2024: Graduate student Will Comstock wins best poster award at the Weill Institute retreat!
  • July 2024: Graduate student Bokun Xie wins best poster award at the FASEB Recombination meeting!
  • June 2024: New EMBO Journal paper by graduate student Bokun Xie addresses the long standing question of how DNA damage signaling suppresses gross chromosomal rearrangements. 
  • May 2024: A big welcome to three new graduate students: Shrijan Bhattarai, Khoula Jaber and Deanna Maybee!!! 
  • December 2023: Our commentary in Molecular Cell discusses two intriguing papers reporting that the ATR kinase promotes nuclear envelope rupture. 
  • December 2023: Former postdoc Diego Dibitetto got a position as Principal Investigator at Mario Negri Institute in Milan, Italy, and will be starting his own lab in January 2024. Congratulations Diego! 
  • November 2023:  Graduate student Will Comstock wins best poster award at the EMBO Practical Course on Targeted Proteomics!
  • November 2023: Our new eLife paper by Carolline Ascenção uncovers how the ATR kinase promotes silencing of the XY chromosomes during meiosis to ensure male fertility. 
  • May 2023: Congratulations to graduate student Will Comstock for being awarded an F31 fellowship from the National Cancer Institute – NIH!!! He will develop and apply novel technologies to monitor DNA damage signaling responses and uncover anti-cancer drug synergies.
  • May 2023: Congratulations to undergraduate student Yiseo Rho and her graduate student mentor Will Comstock for the best poster award at the CURB symposium.
  • March 2023: Congratulations to graduate student Jumana Badar for receiving The Harry & Samuel Mann Outstanding Graduate Student Award !!!
  • September 2022: Our new paper in Molecular Cell reports a suprising role for the DNA-PKcs kinase in DNA replication, with implication for understanding chemoresistance.  
  • August 2022: Congratulations to postdoc Jason Wang for receiving the Postdoctoral Fleming Fellowship!!
  • May 2022: Congratulations to graduate student Jumana Badar for
    receiving the Community Outreach Award and being nominated for the Excellence in Leadership Award!!
  • May 2022: Congratulations to graduate student Will Comstock for receiving the CALS Outstanding Teaching Assistant Award!!
  • March 2022: Congratulations to Carolline Ascenção for receiving the ASCB International Training Scholarship!!
  • February 2022: Our new work in eLife reveals the ATR signaling network in mammalian meiosis.

Previous Lab News

Statement on Diversity, Equity and Inclusion. The Smolka Lab welcomes all individuals regardless of gender, sexual orientation, age, race/ethnicity, religion, cultural background, or socioeconomic status. We are a group of scientists with a diverse background, committed to speak out against racism and intolerance, anywhere. We understand that much effort is still needed to make Academia an inclusive space and are dedicated to promoting a sense of belonging. By participating in workshops, group discussions and initiatives such as the MBG Diversity Council, we aim to continuously improve our awareness about key issues in diversity, equity and inclusion, and better understand of our own unconscious biases.

 

Research Projects

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

Signaling networks required for genome integrity, and their connections to oncogenesis, therapy and reproduction. We are investigating how the actions of kinases are translated into a coordinated cellular response that ensures proper maintenance and replication of the genome. Our recent work in yeast and mammalian systems uncovered how phosphorylation events mediated by DNA damage signaling kinases form a “code” of combinatorial protein interactions leading to a range of distinct functional outputs in the control of DNA replication, cell cycle and DNA repair. Recent work is also beginning to bridge our fundamental work toward potential clinical implications, including studies on the rational use of inhibitors of DNA damage kinases to manipulate DNA repair systems in cancer cells. We are also mapping the action of DNA damage signaling kinases in mammalian meiosis to define their roles in preventing infertility.

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 in a range of cellular systems and tissues.

 

We are grateful for the funding provided by:

American_Cancer_Society_Logo

NIGMS

NIH

NIGMS