RNA damage compartmentalization by DHX9 stress granules

Area of Science:

• Cellular Biology
• Molecular Biology
• Stress Response

Background:

• Biomolecules are susceptible to damage under stress conditions.
• Damage partitioning is a critical survival mechanism for cells.
• Classical stress granules (SGs) are known to form during cellular stress.

Purpose of the Study:

• To identify and characterize novel stress granules involved in damage partitioning.
• To investigate the role of DHX9 in the formation and function of these stress granules.
• To understand the mechanism by which these SGs protect daughter cells from parental damage.

Main Methods:

• Utilized FANCI technology to analyze RNA and DNA damage within stress granules.
• Investigated the composition of DHX9-marked stress granules.
• Examined the effects of UV exposure on RNA splicing, decay, and SG formation.
• Assessed the role of DHX9 and p62 in SG dynamics and cell viability.

Main Results:

• Identified a distinct DHX9-marked stress granule that compartmentalizes UV-induced RNA damage, specifically damaged intron RNA.
• DHX9 SGs are enriched in damaged intron RNA, unlike classical SGs composed of mature mRNA.
• UV exposure leads to RNA crosslinking, impaired intron splicing and decay, and triggers DHX9 SG formation in daughter cells.
• DHX9 SGs promote cell survival, induce dsRNA-related immune responses, and cause translation shutdown.
• DHX9 modulates dsRNA levels within SGs, enhancing cell viability, and p62 is crucial for DHX9 SG disassembly.

Conclusions:

• Established non-canonical DHX9 SGs as a unique cytoplasmic compartment for managing parental RNA damage.
• DHX9 SGs safeguard daughter cells by sequestering damaged RNA, distinct from classical SGs.
• These findings reveal a novel mechanism of damage partitioning crucial for cellular resilience and survival.