biostudies-literatureMachado de Amorim ADeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)155https://www.ebi.ac.uk/biostudies/studies/S-EPMC12775136biostudies-literatureUnknown17(1)Metazoan histone mRNAs are a unique class of mRNAs that lack the poly(A) tail present in all other eukaryotic transcripts. Instead, they end in a conserved stem-loop (SL) structure, necessitating a decay mechanism that is distinct from deadenylation-initiated degradation. Here, combining structural and functional approaches, we elucidate molecular mechanisms of initiation of histone mRNA decay. At the end of S-phase, the RNA helicase UPF1, the exoribonuclease 3'hExo and stem-loop binding protein SLBP all contribute to histone mRNA degradation, although how they are mechanistically coupled remained unknown. The cryoEM structure of an UPF1:SL RNA complex, presented here, shows that binding of UPF1 partially melts the RNA stem in the absence of ATP, harnessing the free energy derived from RNANature communicationsMechanistic insights into recruitment and regulation of the RNA helicase UPF1 in replication-dependent histone mRNA decay.PMC12775136CH1245/6-1CH1245/3-2CH1245/5-1Xue GDittmers TLewandowski SUrlaub HPerez-Borrajero CHilal TNandana VMachado de Amorim AMarzluff WFMateva NHe WKrage CLoll BHennig JChakrabarti SBethmann JfalseMechanistic insights into recruitment and regulation of the RNA helicase UPF1 in replication-dependent histone mRNA decay.Metazoan histone mRNAs are a unique class of mRNAs that lack the poly(A) tail present in all other eukaryotic transcripts. Instead, they end in a conserved stem-loop (SL) structure, necessitating a decay mechanism that is distinct from deadenylation-initiated degradation. Here, combining structural and functional approaches, we elucidate molecular mechanisms of initiation of histone mRNA decay. At the end of S-phase, the RNA helicase UPF1, the exoribonuclease 3'hExo and stem-loop binding protein SLBP all contribute to histone mRNA degradation, although how they are mechanistically coupled remained unknown. The cryoEM structure of an UPF1:SL RNA complex, presented here, shows that binding of UPF1 partially melts the RNA stem in the absence of ATP, harnessing the free energy derived from RNA2026-01-01T00:00:00Z2026 Jan2026-06-06T11:52:11.585Z2026-05-30T03:09:31.106ZS-EPMC127751364148412910.1038/s41467-025-67991-z