DHX36 maintains genomic integrity by unwinding G-quadruplexes

Area of Science:

• Genomics
• Molecular Biology
• DNA Repair Mechanisms

Background:

• Guanine-rich single-stranded DNA (ssDNA) can form G-quadruplex (G4) structures in chromosomes.
• G4 formation is increased during DNA replication and transcription, and can impede these processes, leading to DNA damage.
• DHX36 is known to unwind G4-DNA, but its in vivo role in genome maintenance is unclear.

Purpose of the Study:

• To investigate the spatial correlation of DHX36 with G4-DNA in vivo.
• To elucidate the role of DHX36 in genome maintenance and its connection to G4-DNA.
• To understand how DHX36 activity impacts DNA damage and cell survival.

Main Methods:

• Examined the nuclear co-localization of DHX36 with G4-DNA, RNA polymerase II, and splicing factors.
• Assessed the effects of DHX36 depletion on DNA damage accumulation and cell growth.
• Evaluated the impact of G4-stabilizing compounds on DHX36-depleted cells.
• Studied the functional rescue by wild-type DHX36 versus G4-binding mutants.

Main Results:

• DHX36 localized to the nucleus, overlapping with G4-DNA and transcription/splicing machinery.
• DHX36 depletion led to increased DNA damage, impaired cell growth, and heightened sensitivity to G4-stabilizing agents.
• DHX36 expression restored normal phenotypes, while mutants unable to bind G4 showed incomplete rescue.

Conclusions:

• DHX36 plays a critical role in suppressing DNA damage by facilitating G4-DNA resolution.
• This G4 resolution by DHX36 is essential for maintaining genomic integrity, promoting cell growth, and ensuring cell survival.
• Findings highlight DHX36 as a key player in genome maintenance through G4-DNA clearance.