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

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Environmental toxins and chemotherapy agents can damage both DNA and RNA.
• While DNA damage repair is well-understood, the consequences of RNA damage are largely unknown.
• Most chemical-induced nucleic acid adducts (>90%) occur in RNA.

Approach:

• Investigated the role of human YTHDC1 protein in response to alkylation damage.
• Examined YTHDC1 binding to modified RNAs (m6A and m1A) after alkylation.
• Assessed the impact of YTHDC1 absence on DNA integrity and sensitivity to alkylation damage.
• Utilized an RNA-specific dealkylase to confirm RNA damage as the cause of observed phenotypes.
• Studied the involvement of R-loop formation and transcription-coupled nucleotide excision repair in RNA damage-induced DNA breaks (RDIBs).

Key Points:

• YTHDC1 binds to N1-methyladenosine (m1A)-containing RNAs upon alkylation.
• Loss of YTHDC1 leads to increased sensitivity to alkylation damage and DNA breaks.
• RNA damage, not DNA damage, causes these phenotypes, as shown by rescue with an RNA dealkylase.
• RNA damage-induced DNA breaks (RDIBs) depend on R-loop formation and transcription-coupled nucleotide excision repair.
• YTHDC1 and THOC prevent RDIBs, highlighting their role in base damage response.

Conclusions:

• Damaged RNA can directly compromise genome integrity.
• YTHDC1, in conjunction with THOC, plays a critical role in preventing RNA damage-induced DNA breaks (RDIBs).
• This study provides the first definitive evidence linking RNA damage to genomic instability through the YTHDC1-THOC pathway.