We are fascinated by how cells organize, protect, and segregate their genomes, and how these fundamental processes are rewired across different cellular contexts. To answer these questions we use mammalian cell lines and a combination of high-resolution microscopy, molecular biology, functional genetics, and large-scale CRISPR-Cas9 screens.

How does the Cohesin complex perform multiple distinct functions in the maintenance of genome integrity?

Overview

The Cohesin complex is essential for genome integrity, contributing to DNA organization, replication, transcription, and cell division. Yet how a single complex performs so many distinct functions remains a fundamental open question. We believe the answer lies in its interactors, the proteins that bind Cohesin and direct its activity across different contexts.

Our lab works to identify and characterize these Cohesin-associated factors, define how Cohesin selectively engages with them, and determine how different combinations drive distinct biological outcomes. Through this work we identified PRR12, a Cohesin-associated factor that regulates complex stability and chromatin organization. Current studies of PRR12 and other interactors are revealing how Cohesin achieves functional diversity and how its misregulation contributes to cancer and developmental disease

Current Projects

  1. Defining the role of Cohesin in the regulation of heterochromatin domains
  2. Determining how Cohesin selects among different binding partners
  3. Separating the selective functions of STAG1 and STAG2 cohesin sub-complexes
  4. Understanding the role of Cohesin in DNA repair

Relevant Publications

Nguyen, A.L. Smith, E., Cheeseman, I.M. (2025). Co-essentiality Analysis Identifies PRR12 as a Cohesin Interacting Protein and a Contributor to Genomic Integrity. Developmental Cell. PMID: 39742660.

How do cells accurately segregate their chromosomes?

Overview

Cell division requires hundreds of proteins to work together in precise coordination to faithfully segregate chromosomes. While this process is essential in all dividing cells, the specific proteins required to execute it can differ dramatically across cell types, developmental states, and disease contexts. Understanding why certain proteins become critical in some cellular contexts but dispensable in others reveals fundamental principles about how the cell division machinery is organized and regulated.

By harnessing these context-specific gene requirements, we uncovered the function of the CENP-O complex and identified why these proteins are selectively required in certain cancers. Current work expands on these findings, defining the function of other selectively required cell division genes and exploring how these contextual differences can be exploited therapeutically.

Current Projects

  1. Defining the role of CK2 in mitosis
  2. Uncovering the selective requirement for SGO2 in cancer

Relevant Publications

  1. Nguyen, A.L. Fadel, M.D., Cheeseman, I.M. (2021). “Differential Requirements for the    CENP-O Complex Reveal Parallel PLK1 Kinetochore Recruitment Pathways”. Molecular Biology of the Cell. 32(8):712-721. PubMed PMID: 33596090.
  2. Blengini, C.S., Nguyen, A.L., Aboelenain, M., Schindler K. (2022). “Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B”. Aging Cell. 20(11). e13489. PubMed PMID: 34704342.
  3. Nguyen, A.L., Drutovic, D., Gentilello, A., Malumbres, M., Solc, P., Schindler K.  (2018). “Genetic interactions between the Aurora kinases reveal new requirements for AURKB and AURKC during oocyte meiosis”. CurrentBiology. 28 (21): 3458-3468 PubMed PMID: 30415701.
  4. Nguyen, A.L., Gentilello A., Balboula A., Shrivastava V., Ohring J., Schindler K. (2014). “Phosphorylation of Threonine 3 on Histone 3 by Haspin Kinase is Required  for Meiosis I in Mouse Oocytes”. Journal of Cell Science.127(23): 5066-5078.  PubMed PMID: 25315835.

Evolutionary Rewiring

Mice and other mammals are routinely used as models for human disease, with the assumption that core cellular processes are highly conserved. Yet our work and others have revealed striking differences in gene requirements across even closely related mammalian species. Understanding these differences illuminates fundamental biology and provides critical insight into the evolution of core cellular processes.

We are pursuing this using pooled CRISPR-Cas9 functional genetic screens in cell lines from diverse animal models, building a comparative map of how genome integrity mechanisms have diverged across species.

Current Projects

  1. Differential regulation of mitotic checkpoints across species
  2. Uncovering the role of the CENPO complex across species

Relevant Publications

  1. Dudka, D., Nguyen, A.L., Boese, K., Marescal, O. Akins, B., Black, B.E., Cheeseman, I.M., Lampson, M.A. (2025) Bi-directional modulation of centromere binding via evolutionary innovation in the CENPT histone fold domain. Current Biology. PMID: 39947176.