Houseley Group

Houseley Group
Houseley Group
Jon Houseley
Group Leader and Head of Knowledge Exchange & Commercialisation
Houseley Group

Research Summary

We study the mechanisms by which cells learn to thrive in new environments.
 
From yeast caught by the wind and scattered across the landscape or plankton dwelling in increasingly acidified oceans to malignant cells facing modern targeted anticancer drugs, cells often face a stark choice – adapt or die.
 
We study the mechanisms by which cells adapt to new environments. A major focus is the unexpected ability of cells to change specific parts of their genomes in response to particular environments. The ability to stimulate mutation at the right time and place is likely to allow organisms to evolve and adapt much faster than we might expect, and such mechanisms have clear medical importance.
 
Attempting adaptive change is dangerous for any organism, and must be tightly controlled within the life cycle. We are starting to discover connections between adaptation and ageing; we have found that cellular ageing can facilitate adaptation, and conversely we see evidence that the drive to adapt to the environment seems to impact the ageing process.
 
Jon is a Wellcome Trust Senior Research Fellow.
 

Latest Publications

Channathodiyil P, May K, Segonds-Pichon A, Smith PD, Cook SJ, Houseley J Epigenetics, Signalling, Bioinformatics

Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that amplifications acquired are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through gene amplification and can be suppressed by impeding cell cycle entry in drug.

+view abstract NAR cancer, PMID: 36267209 Dec 2022

Nunes C, Depestel L, Mus L, Keller KM, Delhaye L, Louwagie A, Rishfi M, Whale A, Kara N, Andrews SR, Dela Cruz F, You D, Siddiquee A, Cologna CT, De Craemer S, Dolman E, Bartenhagen C, De Vloed F, Sanders E, Eggermont A, Bekaert SL, Van Loocke W, Bek JW, Dewyn G, Loontiens S, Van Isterdael G, Decaesteker B, Tilleman L, Van Nieuwerburgh F, Vermeirssen V, Van Neste C, Ghesquiere B, Goossens S, Eyckerman S, De Preter K, Fischer M, Houseley J, Molenaar J, De Wilde B, Roberts SS, Durinck K, Speleman F Epigenetics, Bioinformatics

High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.

+view abstract Science advances, PMID: 35857500 15 Jul 2022

Whale AJ, King M, Hull RM, Krueger F, Houseley J Epigenetics

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 can cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32 and Pif1. CUP1 amplification is also critically dependent on late-firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after activation, leaving a tract of H3K56-acetylated chromatin that promotes secondary recombination events during elongation after replication fork re-start events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.

+view abstract Nucleic acids research, PMID: 35018465 08 Jan 2022

bioRxiv Manuscripts

DNA REPLICATION DURING ACUTE MEK INHIBITION DRIVES ACQUISITION OF RESISTANCE THROUGH AMPLIFICATION OF THE BRAF ONCOGENE
Prasanna Channathodiyil, Anne Segonds-Pichon, Paul D. Smith, Simon J. Cook, Jonathan Houseley
bioRxiv 2021.03.23.436572
https://doi.org/10.1101/2021.03.23.436572

STIMULATION OF ADAPTIVE GENE AMPLIFICATION BY ORIGIN FIRING UNDER REPLICATION FORK CONSTRAINT
Alex J. Whale, Michelle King, Ryan M. Hull, Felix Krueger, Jonathan Houseley
bioRxiv 2021.03.04.433911
https://doi.org/10.1101/2021.03.04.433911

Group Members

Jon Houseley

Group Leader and Head of Knowledge Exchange & Commercialisation

Hanane Hadj-Moussa

Postdoc Research Scientist

Dorottya Horkai

Visiting Scientist

Neesha Kara

PhD Student

Kieron May

PhD Student

Alex Whale

Postdoc Research Scientist