NAT 10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2

Abstract

As a genome guardian, p53 maintains genome stability by arresting cells for damage repair or inducing cell apoptosis to eliminate the damaged cells in stress response. Several nucleolar proteins stabilize p53 by interfering Mdm2-p53 interaction upon cellular stress, while other mechanisms by which nucleolar proteins activate p53 remain to be determined. Here, we identify NAT10 as a novel regulator for p53 activation. NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity. After DNA damage, NAT10 translocates to nucleoplasm and activates p53-mediated cell cycle control and apoptosis. Finally, NAT10 inhibits cell proliferation and expression of NAT10 decreases in human colorectal carcinomas. Thus, our data demonstrate that NAT10 plays a critical role in p53 activation via acetylating p53 and counteracting Mdm2 action, providing a novel pathway by which nucleolar protein activates p53 as a cellular stress sensor.

Clonal evolution analysis of paired anaplastic and well‐differentiated thyroid carcinomas reveals shared common ancestor

“…In patients 309, 310, and 401, mutations from known cancer/MMR drivers were observed in the shared ancestral VAF cluster, including NRAS p.Gln61Arg from 309, BRAF p.Val600Glu from 310, and POLG p.Trp688fs from 401. In patients 312 and 403, although no variants from known cancer genes were found, we did identify rare shared damaging variants in cancer‐related genes NAT10 (a p53 regulator) from patient 312 and ALDH2 (protective to DNA damage) from patient 403. Key cancer‐related mutations seemed to occur as the origin for both ATCs and WDTC.…”

Acetylation of Cytidine in mRNA Promotes Translation Efficiency

“…Of note, NAT10 was previously described as a protein acetyltransferase with demonstrated activities against α-tubulin, histones and p53 (Larrieu et al, 2014; Liu et al, 2016; Lv et al, 2003; Shen et al, 2009). In contrast to the dramatic reduction observed in ac4C levels, immunoblotting with acetyl-specific antibodies showed little change in protein acetylation in NAT10−/− as compared to wildtype HeLa cells (Figure S1J).…”

p53 Specifically Binds Triplex DNA In Vitro and in Cells

“…Recently, NAT10 was described as a protein regulating p53 activation through its acetylation and also that NAT10 was upregulated under stress conditions in a p53-dependent manner. Thus, NAT10 forms a positive regulation feedback with p53 in response to stress [84]. …”