No abstract

Backgroundp53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy.Principal FindingsLive cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%.Conclusionsp53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway.

No abstract

Induced pluripotent stem (iPS) cells have greatly provoked people's interest due to their enormous potential of clinical applications. Increasing care is taken with the genetic safety of iPS cells. However, up to now, the chromosomal integrity of murine iPS (miPS) cells has been largely unknown. We have observed recurrent trisomy and/or Robertsonian translocation (Rb) of chromosome 14 in six out of nine independent miPS cell lines from three laboratories by G-banding, fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) analyses, while all the miPS cell lines were derived from mouse embryonic fibroblasts (MEFs) or neural precursor cells (NPCs) with a normal karyotype. The miPS cells with trisomy and/or Rb of chromosome 14 showed growth advantage over the miPS cells with a normal karyotype. We found a significantly higher frequency of Rbs in the miPS cell lines induced with c-Myc than those without c-Myc. Our findings demonstrate that miPS cell lines have the propensity for chromosomal aberrations and there is an obvious correlation between the extent of chromosomal aberrations in miPS cells and the transcriptional factors used for their reprogramming. Therefore, our study raises awareness of the need for improvements of the induction conditions of miPS cells in order to avoid the chromosomal aberrations and ensure future safe applications.

The continuous spread of the newly emerged SARS-CoV-2 Omicron variant (B.1.1.529) has become an important reason for the surge in COVID-19 infections. Its numerous mutated residues containing key sites on...

Coronavirus disease 2019 (COVID-19), which is caused by a new coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading around the world. However, universally effective treatment regimen...

Convenient and efficient therapeutic agents are urgently needed to block the continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, the mechanism for the novel orally targeted SARS-CoV-2 main protease (Mpro) inhibitor S-217622 is revealed through a molecular dynamics simulation. The difference in the movement modes of the S-217622–Mpro complex and apo-Mpro suggested S-217622 could inhibit the motility intensity of Mpro, thus maintaining their stable binding. Subsequent energy calculations showed that the P2 pharmacophore possessed the highest energy contribution among the three pharmacophores of S-217622. Additionally, hot-spot residues H41, M165, C145, E166, and H163 have strong interactions with S-217622. To further investigate the resistance of S-217622 to six mainstream variants, the binding modes of S-217622 with these variants were elucidated. The subtle differences in energy compared to that of the wild type implied that the binding patterns of these systems were similar, and S-217622 still inhibited these variants. We hope this work will provide theoretical insights for optimizing novel targeted Mpro drugs.

Inhibitors that competitively bind MDM2/MDMX can block the inhibition of P53 by MDM2/MDMX and restart its tumor-suppressive effect. Molecular studies targeting MDM2/MDMX inhibitors have always been a hot topic in...