RESUMEN
The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. This results in CaMKK2/AMPK activation and subsequent Exo1 phosphorylation, which prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here, through a genome-wide CRISPR-based screen, we identify TRPM8 channel-associated factor 1 (TCAF1) as a key factor promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 assists Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress.
Asunto(s)
Calcio , Citosol , Replicación del ADN , Proteínas de la Membrana , Canales Catiónicos TRPV , Humanos , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Calcio/metabolismo , Citosol/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células HEK293 , ADN/metabolismo , Células HeLa , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Fosforilación , Inestabilidad Genómica , Daño del ADN , AnimalesRESUMEN
This full-length genome sequence of human enterovirus strain 71 (EV71/Taipei/3118/2011) was isolated from a clinical patient in Taiwan in 2011. According to the phylogenetic analysis, the complete genome sequence in this study is part of the subgenotype C4.