Non-genotoxic activation of p53 through the RPL11-dependent ribosomal stress pathway.

Nucleolar disruption has recently emerged as a relevant means to activate p53 through inhibition of HDM2 by ribosome-free RPL11. Most drugs that induce nucleolar disruption also possess important genotoxic activity, which can have lasting mutagenic effects. Therefore, it is of interest to identify compounds that selectively produce nucleolar disruption in the absence of DNA damage. Here, we have performed a high-throughput screening to search for nucleolar disruptors. We have identified an acridine derivative (PubChem CID-765471) previously known for its capacity to activate p53 independently of DNA damage, although the molecular mechanism underlying p53 activation had remained uncharacterized. We report that CID-765471 produces nucleolar disruption by inhibiting ribosomal DNA transcription in a process that includes the selective degradation of the RPA194 subunit of RNA polymerase I. Following nucleolar disruption, CID-765471 activates p53 through the RPL11/HDM2 pathway in the absence of detectable DNA damage. In a secondary screening of compounds approved for medical use, we identify two additional acridine derivatives, aminacrine and ethacridine, that operate in a similar manner as CID-765471. These findings provide the basis for non-genotoxic chemotherapeutic approaches that selectively target the nucleolus.

Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.

A-type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A-type lamins and how they contribute to disease are poorly understood. Here, we show that A-type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A-type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A-type lamins are necessary for the processing of dysfunctional telomeres by non-homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A-type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin-related diseases.

Judith Agudo: Beware of your inner self-immune attack.

Judith Agudo studies the mechanisms that adult and cancer stem cells use to evade the immune response with the goals of engineering autoimmunity- and allograft-resistant stem cells and improving the response of cancer stem cells to immunotherapy.

Gina DeNicola: In vivo veritas.

Gina DeNicola investigates the metabolism of cancer cells in vivo with a focus on NRF2 and the tumor microenvironment.

Yogesh Kulathu: Decoding complex intracellular messages.

Yogesh Kulathu studies signaling mechanisms with a focus on ubiquitin and other post-translational modifications such as UFMylation.

Chii Jou Chan: The positives of being under "pressure".

Chii Jou Chan investigates how tissue hydraulics regulates mammalian development, with a special focus on folliculogenesis and oocyte quality control.

The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma.

The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.

Sara Wickström: The forces controlling our cell fate.

Sara Wickström combines biophysics, next-generation sequencing, and basic cell biology to investigate how cellular forces regulate the fate and position of stem cells within epithelial tissues.

Lena Ho: Micropeptides under the spotlight.

Lena Ho studies small ORF-encoded peptides (SEPs; also known as micropeptides), with a particular focus on mitochondrial SEPs, and their role in vascular biology and immunometabolism.

Sara Cuylen-Haering: Cellular soaps to keep neat chromosomes.

Sara Cuylen-Haering studies the molecular mechanisms driving phase separation of chromosomes and other cellular organelles, with a special focus on biological surfactants.

Bo Zhong: Captive by the viral immune escape.

Bo Zhong studies the regulation of the antiviral innate immunity, inflammation, and tumorigenesis by the protein ubiquitination system.

Ori Avinoam: Mind, body, and membranes in shape.

Ori Avinoam studies membrane remodeling with a focus on cell-to-cell fusion through the lens of correlative light and electron microscopy.

Elvan Böke: Long live the oocyte.

Elvan Böke investigates the mechanisms that preserve the viability of dormant oocytes.

Sachihiro Matsunaga: FISHing the nuclear architecture of plant cells.

Sachihiro Matsunaga studies the nuclear structure and chromatin dynamics of plants.

Rushika M. Perera: Lysosomes unveil what cancer cells hide.

Rushika M. Perera studies how pancreatic cancer cells use autophagy and the lysosome to adapt to stress.

Dorothy Schafer: Sculpting the next generation of microglia researchers.

Dorothy Schafer investigates the role of microglia in neural circuit development and plasticity with a special focus on neurological disorders.

Elda Grabocka: Stress-buffering comes in granules.

Elda Grabocka investigates the role of stress granules in obesity and cancer.

Nan Yan: Innate immune signaling goes beyond viral.

Nan Yan studies the physiological function of innate immune signaling in the absence of pathogen infection.

Vaishnavi Ananthanarayanan: Advocating for women's representation in science.

Vaishnavi Ananthanarayanan investigates the regulation of motor proteins and cytoskeleton-organelle interactions using single-molecule microscopy.

Gaia Pigino: Inside the cell.

Gaia Pigino studies the molecular mechanisms and principles of self-organization in cilia using 3D cryo-EM.