MRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability

Here, we demonstrate that the proximal polyadenylation site (pPAS) of MRE11 engages in PAS-promoter looping to facilitate RNA polymerase recycling and maintain high promoter activity, a mechanism not well characterized in mammals. Deletion of the MRE11 pPAS disrupts this looping, reduces MRE11 transcription, impairs MRN complex levels, and phenocopies hypomorphic MRE11 mutations.

MRE11pPAS-/- cells exhibit ectopic DNA replication and reduced viability under overgrowth conditions. EdU-seq revealed that aberrant DNA synthesis in MRE11pPAS-/- cells occurs primarily at intronic and intergenic regions. MRE11 ChIP-seq showed decreased binding at these regions, correlating with elevated DNA replication.