Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), has spread widely around the globe. Significant inter-individual differences have been observed during the course of the infection, which suggests that genetic susceptibility may be a contributing factor. CC chemokine receptor 5 (CCR5), which acts as a co-receptor for the entry of HIV-1 into cells, is promising candidate whose can have an influence on SARS-CoV-2 infection. A genetic mutation known as CCR5Δ32, consisting of a 32-nucleotide deletion, encodes a truncated protein that protects homozygous carriers of the deletion from HIV-1 infection. Similarly, inhibition of CCR5 seems to be protective against COVID-19. In our study, we successfully genotyped 416 first-wave SARS-CoV-2-positive infection survivors (164 asymptomatic and 252 symptomatic) for CCR5Δ32, comparing them with a population based sample of 2,404 subjects. We found the highest number (P=0.03) of CCR5Δ32 carriers in SARS-CoV-2-positive/COVID-19-asympto-matic subjects (23.8 %) and the lowest number in SARS-CoV-2-positive/COVID-19-symptomatic patients (16.7 %), with frequency in the control population in the middle (21.0 %). We conclude that the CCR5Δ32 I/D polymorphism may have the potential to predict the severity of SARS-CoV-2 infection.

Fusarium culmorum is a phytopathogenic fungus causing Fusarium head blight (FHB), which negatively affects cereals by producing mycotoxins, such as deoxynivalenol (DON). In this work, two barley cultivars, Chevron and Pedant, with different degrees of resistance to FHB were inoculated with F. culmorum. The transcription levels of the Fusarium Tri genes and barley UDP‐glycosyltransferase genes were investigated. The amounts of pathogen, DON and the detoxification product deoxynivalenol‐3‐O‐glucoside (D3G) were monitored. The greatest amounts of pathogen were detected at 21 days postinoculation (dpi) and were much lower in cv. Chevron than in cv. Pedant. No differences in the total DON conversion to D3G were observed between the cultivars. Ubiquitin‐conjugating enzyme (UBC) was identified and then used as a reference gene to monitor transcription of the Fusarium Tri genes in infected barley. Transcription of the F. culmorum Tri5, Tri4, Tri6 and Tri10 genes differed between the two cultivars. In the susceptible cultivar (Pedant), transcription of the Tri genes gradually increased from 1 dpi. In the more resistant Chevron, transcription of the Tri genes dramatically increased after 14 dpi and reached a maximum at 21 dpi. This very high but delayed transcription of Tri genes did not, however, result in a large accumulation of the mycotoxin DON. The difference between the cultivars in the transcription of barley defence genes (HvUGT13248 [GT2] and HvUGT5876 [GT1]) for UDP‐glycosyltransferases reflects the barley samples’ levels of infection. The difference in resistance to F. culmorum infection in the two cultivars is most likely not due to differences in DON detoxification, but may be due to activity against the pathogen and delayed transcription of the pathogen's Tri genes.

The transcription activities of genes somehow associated with the mycotoxin deoxynivalenol (DON) biosynthesis, namely Fusarium Tri genes, and the barley gene coding for UDP-glycosyltransferase (HvUGT13248) on different genetic backgrounds were compared. Determining the amount of the pathogen DNA was used as a useful tool for evaluating the infestation of barley cultivars. Amounts of the pathogen DNA differed in six barley cultivars infected by F. culmorum. Transcription of HvUGT13248 was related to DON content in the samples. Low pathogenic infection and low DON content were accompanied by increased Fusarium Tri10 transcription in resistant cv. Amulet. This finding confirmed our recent results and makes us propose using this change as a possible marker of barley resistance against Fusarium.

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