The tumour suppressor CYLD regulates the p53 DNA damage response

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• The tumor suppressor CYLD is a deubiquitinase known to inhibit NF-κB, MAP kinase, and Wnt signaling pathways.
• The precise mechanisms underlying CYLD's tumor-suppressive functions are not fully elucidated.

Purpose of the Study:

• To investigate the role of CYLD in DNA damage response and its contribution to tumor suppression.
• To elucidate the molecular mechanisms by which CYLD regulates p53 stability and activation.

Main Methods:

• Assessed the impact of CYLD catalytic activity loss on p53 stabilization and activation in epithelial cells.
• Utilized mouse models to evaluate sensitivity to chemical carcinogen-induced tumorigenesis.
• Employed ubiquitin chain-restriction analysis to study CYLD's deubiquitinating activity on p53.
• Examined CYLD's function in DNA damage-induced germ cell apoptosis in Caenorhabditis elegans.

Main Results:

• Loss of CYLD catalytic activity impairs DNA damage-induced p53 stabilization and activation in epithelial cells.
• CYLD deficiency sensitizes mice to chemical carcinogen-induced intestinal and skin tumorigenesis.
• CYLD directly interacts with and deubiquitinates p53, facilitating its stabilization under genotoxic stress.
• CYLD removes K48 ubiquitin chains from p53 indirectly by cleaving K63 linkages, indicating complex ubiquitinylation of p53.
• CYLD deficiency reduces CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in C. elegans.

Conclusions:

• CYLD acts as a deubiquitinase that facilitates DNA damage-induced p53 activation.
• Regulation of p53 responses to genotoxic stress is a key mechanism contributing to CYLD's tumor suppressor function.