Nature Communications最新文献

p53 is crucial for cellular functions and disease mechanisms, yet effective clinical strategies targeting it remain challenging. Lactylation has emerged as a key factor in understanding disease pathology and offering therapeutic options. Herein, we identify lactylated KAT8 at lysine 145 (K145) as a modulator of p53 activity. GCN5 and SIRT6 function as the acyltransferase and delactylase for KAT8, respectively. K145 lactylation fosters the formation of KAT8-TIP60 complex, which couples with p53 to facilitate its acetylation at lysine 120 (K120). The KAT8-TIP60 complex promotes K120-acetylated p53 binding to the BAX and PUMA promoters, activating their transcription. Furthermore, we link KAT8 lactylation to doxorubicin-induced cardiotoxicity (DIC), showing that doxorubicin increases K145 lactylation, amplifying p53's pro-apoptotic function and triggering cardiomyocyte apoptosis. Glimepiride, a therapeutic agent for type 2 diabetes, could target KAT8, disrupt its interaction with GCN5, inhibit KAT8 K145 lactylation, and mitigate DIC. These findings provide insight into how KAT8 K145 lactylation modulates p53 activity and contributes to DIC.

Ibiza, an island in present-day Spain, was conquered in 902 CE by the Umayyad Emirate of Córdoba. The island remained under Islamic rule until 1235. Here, we analyse the genetic and metagenomic profiles of 13 individuals from an Islamic cemetery in Ibiza, dated to 950-1150 CE. Genome-wide analyses reveal heterogeneity, with ancestry components from Europe, North Africa, and Sub-Saharan Africa. Our analyses estimate that North African gene flow occurred two to seven generations before these individuals lived, suggesting admixture following the Islamic conquest of Iberia and potentially on Ibiza itself. Notably, two individuals trace their Sub-Saharan origins to distinct regions, Senegambia and present-day southern Chad, providing direct evidence of trans-Saharan connections via military and slave networks documented in contemporary Arabic sources. Metagenomic analyses detect several pathogens in this community, with one individual carrying Mycobacterium leprae, offering insight into the presence of leprosy in Ibiza. Our findings align with the historically documented two-pulse demographic model, indicating an initial settlement following the early tenth-century conquest and a second influx associated with Almoravid movements in the twelfth century. These securely dated genomes offer insights into medieval population dynamics and health in the Balearics.

During spermatogenesis, the unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI) and form a heterochromatic XY body. Defects in MSCI lead to meiotic arrest and male infertility. Although DNA damage response (DDR) factors are established as key initiators of MSCI, how transcriptional silencing is subsequently achieved remains elusive. Here, we identify the nucleolar components NPM1, SENP3, and rRNA as essential downstream effectors of DDR signaling in MSCI. During pachytene, these components migrate to and transiently cover the XY body during MSCI establishment, before becoming restricted to a corner of the XY body. Genetic deletion of Npm1 or Senp3, or inhibition of rRNA transcription severely impairs MSCI. Mechanistically, SENP3-mediated deSUMOylation of NPM1 promotes its interaction with rRNA, enabling liquid-liquid phase separation, via which they exclude Pol II from the XY body. Together, these data reveal a critical role of nucleolar components in the transcriptional regulation of MSCI in mammalian spermatogenesis.