GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE267nnn/GSE267579/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE267579GEOGSEfalseMRE11 proximal polyadenylation site-mediated looping impacts transcription and genomic stability [RNA-seq]MRE11, a key regulator in maintaining genome integrity, has two main polyadenylation sites (PAS) in 3’UTR. There is a ~3 Kb difference between the proximal PAS (pPAS) and the distal PAS (dPAS). Therefore, using the pPAS can result in a ~3 Kb shorter MRE11 transcript which lacks a significant number of regulatory motifs in the 3’UTR. Analysis of the Cancer Genome Atlas revealed (10/160) mutations in MRE11 3’UTR, and intriguingly all these mutations are localized in pPAS. We observed that deletion of pPAS (~150 bp) using CRISPR caused ~50% reduction of MRE11 protein and mRNA. We hypothesize that pPAS regulates transcription of the MRE11 gene via ‘DNA looping’ where this cis element in the 3’UTR regulates the canonical MRE11 promoter. MRE11 hypomorphism in AT-like deficiency (ATLD) cells is well characterized, and MRE11pPAS-/- phenocopy these cells. Cell cycle analysis revealed that MRE11pPAS-/- cells grow slower with increased proportion of cells in the S/G2 phase with a concurrent decrease in the G0/G1 population. The most intriguing phenotype was in the context of G1/S checkpoint. Overgrown wild-type RPE1 cells when confluent exit the cell cycle and stop replicating. In contrast, MRE11pPAS-/- cells continued replicating leading to rapid cell death. Next, we systematically synchronized cells in G0/G1, and observed that EdU labeling in these G0/G1-paused cells shows increased BrdU+ population only in MRE11pPAS-/- cells. Induction of MRE11 in MRE11pPAS-/- cells can ‘rescue’ the ectopic replication of confluent cells, confirming that the phenotype is indeed due to reduced MRE11 expression. This suggests that optimal MRE11 is necessary for preventing unlicensed DNA replication in completely distinct scenarios. Our study highlights the importance of the 3’UTR in transcriptional regulation of MRE11 and its profound impact on genomic stability and cell growth.2026/04/06GSE267579GSM8269317GSM8269316GSM8269315GSM8269325GSM8269314GSM8269319GSM8269318GSM8269320GSM8269324GSM8269323GSM8269322GSM826932123227267579Homo sapiens