Chromatin-associated MRN complex protects highly transcribing genes from genomic instability

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The MRN-MDC1 complex is crucial for DNA damage response (DDR) and repair.
• Active gene transcription can potentially induce DNA damage.

Purpose of the Study:

• To investigate the role of MRN-MDC1 in the context of active gene transcription.
• To determine how MRN-MDC1 interacts with the transcriptional machinery.

Main Methods:

• Proteomics of isolated chromatin fragments.
• Chromatin immunoprecipitation sequencing (ChIP-seq).
• Depletion studies using RNA interference (RNAi).

Main Results:

• MDC1 associates with actively transcribing genes and interacts with both DDR and gene expression factors.
• MRN subunits (MRE11, NBS1) localize to active gene bodies, dependent on RNAPII.
• MRN depletion leads to increased RNAPII at target genes and induces genetic mutations in active genes.

Conclusions:

• The MRN complex constitutively scans active genes by associating with the transcriptional machinery.
• This scanning mechanism detects and responds to transcription-induced DNA damage, maintaining coding genome integrity.