The Ubiquitin-like with PHD and Ring Finger Domains 1 (UHRF1)/DNA Methyltransferase 1 (DNMT1) Axis is a Primary Regulator of Cell Senescence [Molecular Bases of Disease]

As senescence develops, cells sequentially acquire diverse senescent phenotypes, along with simultaneous multi-stage gene reprogramming. It remains unclear what acts as the key regulator of the collective changes in gene expression at initiation of senescent reprogramming. Here we analysed time-series gene expression profiles obtained in two different senescence models in human diploid fibroblasts (HDF): replicative senescence and H2O2-induced senescence. Our results demonstrated that suppression of DNA methyltransferase 1 (DNMT1)-mediated DNA methylation activity was an initial event prior to the display of senescent phenotypes. We identified seven DNMT1-interacting proteins (DIPs), ubiquitin-like with PHD and ring finger domains 1 (UHRF1), EZH2, CHEK1, SUV39H1, CBX5, PARP1, and HELLS, as being commonly down-regulated at the same time-point as DNMT1 in both senescence models. Knockdown experiments revealed that among the DIPs only UHRF1 knockdown suppressed DNMT1 transcription. However, UHRF1 overexpression alone did not induce DNMT1 expression, indicating that UHRF1 was essential but not sufficient for DNMT1 transcription. While UHRF1 knockdown effectively induced senescence, this was significantly attenuated by DNMT1 overexpression, clearly implicating the UHRF1/DNMT1 axis in senescence. Bioinformatics analysis further identified WNT5A as a downstream effector of UHRF1/DNMT1-mediated senescence. Senescence-associated hypo-methylation was found at base pairs −1569 to −1363 from the transcription start site of the WNT5A gene in senescent HDF. As expected, WNT5A overexpression induced senescent phenotypes. Overall, our results indicated that decreased UHRF1 expression is a key initial event in the suppression of DNMT1-mediated DNA methylation and in the consequent induction of senescence via increasing WNT5A expression.

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