YTHDC1 cooperates with the THO complex to prevent RNA-damage-induced DNA breaks.

Area of Science:

• Molecular Biology
• Genomics
• Cell Biology

Background:

• Environmental toxins and chemotherapeutics can damage DNA and RNA.
• The consequences of RNA damage on cellular functions, particularly genome integrity, are not well understood.
• Most nucleic acid adducts occur in RNA, highlighting the need to study RNA damage effects.

Purpose of the Study:

• To investigate the impact of nuclear RNA damage on genome integrity in human cells.
• To elucidate the mechanisms by which RNA damage leads to genomic instability.
• To identify key proteins involved in regulating cellular responses to RNA damage.

Main Methods:

• Investigated the role of YTHDC1 protein in regulating alkylation damage responses.
• Examined the binding of YTHDC1 to N1-methyladenosine (m1A) modifications in RNA.
• Assessed DNA breaks and sensitivity to alkylation damage in cells with altered YTHDC1 or THO complex (THOC) expression.
• Utilized an RNA-specific dealkylase to assess rescue effects.
• Studied the role of R-loop formation and XPG nuclease in RNA-damage-induced DNA breaks (RDIBs).

Main Results:

• Nuclear RNA damage can lead to a loss of genome integrity in human cells.
• YTHDC1 regulates alkylation damage responses by interacting with the THO complex (THOC).
• YTHDC1 binds to both N6-methyladenosine (m6A) and chemically induced N1-methyladenosine (m1A) in RNA.
• Cells lacking YTHDC1 exhibit increased sensitivity to alkylation damage and DNA breaks.
• These RNA-damage-induced DNA breaks (RDIBs) are dependent on R-loop formation and the XPG nuclease.
• The nuclear RNA m1A methyltransferase can induce DNA breaks in the absence of YTHDC1 or THOC.

Conclusions:

• Damaged nuclear RNA can directly impact and compromise genomic integrity.
• YTHDC1 plays a critical role in cellular defense against RNA damage, preventing DNA breaks.
• The study reveals a novel pathway where RNA damage, R-loop formation, and XPG activity lead to DNA breaks.
• These findings provide mechanistic insights into how RNA damage affects genomic stability.