The UVSSA complex alleviates MYC-driven transcription stress

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Cancer cells rely on genetic dependencies for survival under oncogenic stress.
• MYC is a frequently activated oncogene in cancer, making it a target for therapeutic strategies.
• Understanding MYC's dependencies can reveal synthetic lethality or sickness interactions.

Purpose of the Study:

• To identify genes that, when downregulated, cause synthetic sickness in combination with MYC expression.
• To elucidate the functional role of UVSSA in MYC-dependent transcription and cell survival.
• To explore the therapeutic potential of targeting the MYC-UVSSA interaction.

Main Methods:

• Genome-wide screenings in MYC-expressing cells.
• Knockdown/knockout studies of UVSSA and assessment of cell viability.
• Analysis of ATM/CHK2 activation, RNA polymerase II (RNAPII) activity, and RNAPII ChIP-seq.

Main Results:

• UVSSA knockdown/knockout caused synthetic sickness with MYC expression, correlating with increased genome instability.
• This synthetic sickness was dependent on RNAPII activity but independent of UV-induced DNA damage repair.
• UVSSA knockdown impaired MYC-dependent increases in RNAPII promoter occupancy, affecting RNAPII dynamics.

Conclusions:

• The UVSSA complex is essential for maintaining MYC-dependent RNAPII dynamics and cell survival in MYC-addicted cancer cells.
• UVSSA plays a critical role in regulating RNAPII activity beyond its known function in UV-induced DNA damage repair.
• Targeting UVSSA offers a potential therapeutic strategy for cancers driven by MYC oncogene activation.