A potent nuclear export mechanism imposes USP16 cytoplasmic localization during interphase.

Area of Science:

• Cell Biology
• Molecular Biology
• Epigenetics

Background:

• USP16 (UBP-M) is a histone H2AK119 deubiquitylase (DUB) involved in chromatin regulation and cell cycle progression.
• Evidence suggests USP16 also functions in the cytoplasm, but its nucleo-cytoplasmic transport and regulation remain unclear.

Purpose of the Study:

• To investigate the nucleo-cytoplasmic localization and transport of USP16.
• To elucidate the role of USP16 localization in DNA double-strand break (DSB) repair.

Main Methods:

• Identification of nuclear export signal (NES) and nuclear localization signal (NLS) in USP16.
• Analysis of USP16 localization during different cell cycle phases and after DNA damage.
• Assessment of USP16's impact on DSB repair upon enforced nuclear localization.

Main Results:

• USP16 is predominantly cytoplasmic throughout the cell cycle, actively exported via an identified NES.
• A non-canonical NLS has a minimal role in nuclear import, and USP16 does not accumulate in the nucleus after DNA damage.
• Enforced nuclear localization of USP16 impairs DSB repair, suggesting its exclusion is important for repair processes.

Conclusions:

• USP16 is actively excluded from the nucleus, contrary to previous views.
• USP16's cytoplasmic localization is critical for proper DNA double-strand break repair, potentially through indirect regulation.