Degradation of oligouridylated histone mRNAs: see UUUUU and goodbye

Abstract

During the cell cycle the expression of replication-dependent histones is tightly coupled to DNA synthesis. Histone messenger RNA (mRNA) levels strongly increase during early S-phase and rapidly decrease at the end of it. Here, we review the degradation of replication-dependent histone mRNAs, a paradigm of post-transcriptional gene regulation, in the context of processing, translation, and oligouridylation. Replication-dependent histone transcripts are characterized by the absence of introns and by the presence of a stem-loop structure at the 3' end of a very short 3' untranslated region (UTR). These features, together with a need for active translation, are a prerequisite for their rapid decay. The degradation is induced by 3' end additions of untemplated uridines, performed by terminal uridyl transferases. Such 3' oligouridylated transcripts are preferentially bound by the heteroheptameric LSM1-7 complex, which also interacts with the 3'→5' exonuclease ERI1 (also called 3'hExo). Presumably in cooperation with LSM1-7 and aided by the helicase UPF1, ERI1 degrades through the stem-loop of oligouridylated histone mRNAs in repeated rounds of partial degradation and reoligouridylation. Although histone mRNA decay is now known in some detail, important questions remain open: How is ceasing nuclear DNA replication relayed to the cytoplasmic histone mRNA degradation? Why is translation important for this process? Recent research on factors such as SLIP1, DBP5, eIF3, CTIF, CBP80/20, and ERI1 has provided new insights into the 3' end formation, the nuclear export, and the translation of histone mRNAs. We discuss how these results fit with the preparation of histone mRNAs for degradation, which starts as early as these transcripts are generated.

HuR stabilizes a polyadenylated form of replication‐dependent histone mRNAs under stress conditions

“…At the beginning of the S-phase, nascent RDH pre-mRNAs are cotranscriptionally recognized by an SL-binding protein (SLBP) via its direct association with the SL located in the 39 UTR (7). The U7 small nuclear RNP complex is then recruited onto a histone downstream element (HDE) located downstream of the SL (8,9). Next, the sequence between the SL and HDE is cleaved by a cleavage and polyadenylation specificity factor-73 and then trimmed by exoribonuclease-1, a 39-59 exoribonuclease.…”

“…Mature RDH mRNAs are exported from the nucleus into the cytoplasm to express histone proteins. In contrast, at the end of the S-phase or under genotoxic stress, actively translated RDH mRNAs undergo drastic mRNP remodeling for rapid mRNA degradation (9,10).…”

Translation initiation mediated by nuclear cap-binding protein complex

“…Upon entry into the S phase, the levels of RDH mRNAs increase by approximately 35-fold at the transcriptional level (68). Newly synthesized RDH transcripts are processed into mature RDH mRNAs with the aid of (i) U7 small nuclear ribonucleoprotein (U7 snRNP), which interacts with histone downstream element (HDE), (ii) stem-loop binding protein (SLBP), which directly binds to the histone stem-loop (HSL) located in the 3′UTR, and (iii) a 3′-end cleavage complex containing cleavage and polyadenylation specificity factor subunit 73 (CPSF73), CPSF100, and symplekin (69, 70). The site between the HSL (recognized by SLBP) and the HDE (base-paired with U7 snRNA) is cleaved by CPSF73 and further trimmed by ERI1, a 3′-to-5′ exonuclease.…”

“…The resulting RDH mRNAs, which have a HSL instead of a poly(A) tail, are exported from the nucleus to the cytoplasm for translation. On the other hand, at the end of S phase or under genotoxic stresses, actively translating RDH mRNAs are rapidly degraded via hyperphosphorylation of UPF1, which recruits various mRNA degradation factors to RDH mRNAs (70–72). …”

Uridylation and adenylation of RNAs

“…Following the oligouridylation event, the heteroheptameric Lsm1–7 complex binds to the oligo(U) tail to trigger subsequent histone mRNA degradation via both 5′–3′ and 3′–5′ RNA decay pathways [10,12]. The C-terminal extension of Lsm4 interacts directly with the 3′ end of the histone mRNP and this interaction is required for efficient histone mRNA degradation [13].…”