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SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis

Akane Ogawa1, Keiichi Izumikawa2, Sota Tate3

  • 1Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan.

Molecular Cell
|February 5, 2025
PubMed

Insights

Schlafen 11 (SLFN11) triggers cancer cell death by impairing ribosome biogenesis (RiBi), a process vital for cell survival. This impairment depletes key proteins like MCL1, leading to apoptosis independent of TP53.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Death Mechanisms

Background:

  • Ribosome biogenesis (RiBi) is crucial for cell function and is often dysregulated in cancer.
  • Inhibition of RiBi can trigger various cellular responses, including apoptosis.
  • Schlafen 11 (SLFN11) is a protein implicated in cellular stress responses.

Purpose of the Study:

  • To investigate the role of SLFN11 in inducing apoptosis through the impairment of ribosome biogenesis.
  • To elucidate the molecular mechanisms by which SLFN11 affects RiBi and cell survival.
  • To determine if RiBi impairment is a general mechanism for SLFN11-mediated cancer cell death.

Main Methods:

  • Replication stress induction in cancer cell lines.
  • Analysis of rRNA synthesis and processing.
  • Assessment of RNA polymerase I activity and chromatin accessibility.
  • Protein depletion studies, focusing on short-lived proteins like MCL1.
  • Functional analysis of SLFN11 domains (Walker B motif, DNA-binding, dephosphorylation, RNase sites).
  • Testing of direct RNA polymerase I inhibitors and other RiBi inhibitors.
  • Evaluation across a panel of 34 human cancer cell lines.

Main Results:

  • SLFN11 inhibits rRNA synthesis and processing, leading to RiBi impairment.
  • This impairment is associated with RNA polymerase I accumulation and increased rDNA chromatin accessibility.
  • SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, notably MCL1.
  • Specific functional domains of SLFN11 are essential for mediating RiBi impairment.
  • RiBi impairment effectively reduces MCL1 levels and induces TP53-independent apoptosis.
  • Comparable apoptotic effects were observed with direct RiBi inhibitors, irrespective of SLFN11 presence.
  • The findings were validated across a diverse range of 34 human cancer cell lines.

Conclusions:

  • Ribosome biogenesis (RiBi) impairment is a potent mechanism for inactivating MCL1 and inducing apoptosis.
  • SLFN11 utilizes RiBi impairment as a TP53-independent proapoptotic pathway.
  • SLFN11 sensitizes cancer cells to chemotherapeutic agents by inducing RiBi impairment.
  • RiBi impairment represents a robust strategy for cancer therapy.
Keywords:
DNA damageTP53apoptosiscell cycle checkpointchromatinrRNAreplication stressribosome biogenesisstress responsetopoisomerase inhibitor

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