Coordinated post-transcriptional control of oncogene-induced senescence by UNR/CSDE1

Area of Science:

• Molecular Biology
• Cell Biology
• Oncology

Background:

• Oncogene-induced senescence (OIS) is a critical tumor-suppressive mechanism involving cell-cycle arrest.
• Understanding OIS establishment and bypass is crucial for cancer research, particularly post-transcriptional regulation.
• The role of RNA-binding proteins in OIS remains largely unexplored.

Purpose of the Study:

• To investigate the role of the RNA-binding protein UNR/CSDE1 in oncogene-induced senescence (OIS).
• To elucidate the molecular mechanisms by which CSDE1 regulates OIS establishment and bypass.
• To determine the tumor suppressor function of CSDE1 in keratinocytes.

Main Methods:

• Depletion of CSDE1 in primary mouse keratinocytes.
• High-throughput analyses to identify CSDE1 targets.
• Assessment of senescence markers, cell proliferation, and tumor formation.
• Investigating mRNA stability and translation regulation.

Main Results:

• CSDE1 depletion abrogates OIS, leading to cell immortalization and tumor formation, identifying CSDE1 as a tumor suppressor.
• CSDE1 enhances the stability of senescence-associated secretory phenotype (SASP) factor mRNAs.
• CSDE1 represses Ybx1 mRNA translation, and YBX1 depletion rescues senescence and uncouples proliferation arrest from SASP.

Conclusions:

• CSDE1 plays a critical role in establishing OIS through dual post-transcriptional mechanisms.
• CSDE1 acts as a tumor suppressor by preventing senescence bypass and immortalization.
• These findings highlight the significance of post-transcriptional control in regulating cellular senescence and tumor suppression.