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

Ryu, Incheol; Park, Yeonkyoung; Seo, Jwa Won; Park, Ok Hyun; Ha, Hong-Seok; Nam, Jin Wu; Kim, Yoon Ki

doi:10.1096/fj.201800431r

Cited by 6 publications

(8 citation statements)

References 57 publications

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“…However, we noticed that polyadenylated and degraded HIST2H4A mRNA was well represented in PARE-seq data, but barely detected by RNA-seq. Recent reports indicated that a subset of histone genes produces poly(A) mRNAs under a variety of cellular conditions and stress conditions [ 30 , 31 , 32 ]. Our data indicated that a subset of RDH mRNAs was polyadenylated and rapidly degraded in XRN1 -knockdown HeLa cells.…”

Section: Resultsmentioning

confidence: 99%

“…If RDH mRNAs are inappropriately processed at the 3′ ends and contain polyadenylated tails, they are rapidly degraded by AU-rich element-mediated mRNA decay via BRF1 [ 40 ]. Under cellular stresses, such as UV-C irradiation or puromycin treatment, BRF1 is degraded, whereas the association of HuR with the 3′ UTR of polyadenlyated RDH mRNAs increases [ 31 ], thereby stabilizing polyadenylated RDH mRNAs. In the present study, we found that most polyadenylated RDH mRNAs were unstable along with high accumulation of their decay byproducts.…”

Section: Discussionmentioning

confidence: 99%

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Global Analysis of the Human RNA Degradome Reveals Widespread Decapped and Endonucleolytic Cleaved Transcripts

Won

Shin

Park

et al. 2020

IJMS

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RNA decay is an important regulatory mechanism for gene expression at the posttranscriptional level. Although the main pathways and major enzymes that facilitate this process are well defined, global analysis of RNA turnover remains under-investigated. Recent advances in the application of next-generation sequencing technology enable its use in order to examine various RNA decay patterns at the genome-wide scale. In this study, we investigated human RNA decay patterns using parallel analysis of RNA end-sequencing (PARE-seq) data from XRN1-knockdown HeLa cell lines, followed by a comparison of steady state and degraded mRNA levels from RNA-seq and PARE-seq data, respectively. The results revealed 1103 and 1347 transcripts classified as stable and unstable candidates, respectively. Of the unstable candidates, we found that a subset of the replication-dependent histone transcripts was polyadenylated and rapidly degraded. Additionally, we identified 380 endonucleolytically cleaved candidates by analyzing the most abundant PARE sequence on a transcript. Of these, 41.4% of genes were classified as unstable genes, which implied that their endonucleolytic cleavage might affect their mRNA stability. Furthermore, we identified 1877 decapped candidates, including HSP90B1 and SWI5, having the most abundant PARE sequences at the 5′-end positions of the transcripts. These results provide a useful resource for further analysis of RNA decay patterns in human cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Global Analysis of the Human RNA Degradome Reveals Widespread Decapped and Endonucleolytic Cleaved Transcripts

Won

Shin

Park

et al. 2020

IJMS

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“…Thus, despite loss of H3.3, H3 levels are maintained up to 6 mo postnatally, suggesting that H3 proteins can be produced from a non-H3.3 source in neurons in the absence of H3f3a / b . Interestingly, although H3.1 and H3.2 genes are thought to be exclusively expressed in S-phase, there is emerging evidence that under certain scenarios, canonical histone genes can be expressed as polyadenylated transcripts in postmitotic cells ( 82 , 83 ). It is important to note that although this potential alternate source of H3 may be able to maintain H3 levels over the long term, it is unable to functionally compensate for loss of initial postmitotic H3.3 accumulation in new neurons, as evidenced by the severe transcriptomic and phenotypic consequences in dKO-N.…”

Section: Discussionmentioning

confidence: 99%

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

Funk

Qalieh

Doyle

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately postmitosis. Codeletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from 1) cycling neural progenitor cells, 2) neurons immediately postmitosis, or 3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, codeletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately postmitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.

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“…In addition to the presence of AREs in the 3′ UTR of mRNAs, recent studies using transcriptome analysis techniques and computational biology approaches have revealed the existence of intronic AREs sequences present on pre-mRNAs in the cell nucleus [ 52 , 99 , 100 , 101 , 102 , 103 ]. To date, understanding the roles of intronic AREs in classic functions of AU-RBPs stabilising or destabilising RNA transcripts or effects on mRNA translation are in their infancy.…”

Section: Post-transcriptional Regulation Of Ddr Genes By Au-rbpsmentioning

confidence: 99%

AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity

Sidali

Teotia

Solaiman

et al. 2021

IJMS

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Genome integrity must be tightly preserved to ensure cellular survival and to deter the genesis of disease. Endogenous and exogenous stressors that impose threats to genomic stability through DNA damage are counteracted by a tightly regulated DNA damage response (DDR). RNA binding proteins (RBPs) are emerging as regulators and mediators of diverse biological processes. Specifically, RBPs that bind to adenine uridine (AU)-rich elements (AREs) in the 3′ untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DDR and preserving genome integrity. Here we review eight established AU-RBPs (AUF1, HuR, KHSRP, TIA-1, TIAR, ZFP36, ZFP36L1, ZFP36L2) and their ability to maintain genome integrity through various interactions. We have reviewed canonical roles of AU-RBPs in regulating the fate of mRNA transcripts encoding DDR genes at multiple post-transcriptional levels. We have also attempted to shed light on non-canonical roles of AU-RBPs exploring their post-translational modifications (PTMs) and sub-cellular localization in response to genotoxic stresses by various factors involved in DDR and genome maintenance. Dysfunctional AU-RBPs have been increasingly found to be associated with many human cancers. Further understanding of the roles of AU-RBPS in maintaining genomic integrity may uncover novel therapeutic strategies for cancer.

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

Cited by 6 publications

References 57 publications

Global Analysis of the Human RNA Degradome Reveals Widespread Decapped and Endonucleolytic Cleaved Transcripts

Global Analysis of the Human RNA Degradome Reveals Widespread Decapped and Endonucleolytic Cleaved Transcripts

Postmitotic accumulation of histone variant H3.3 in new cortical neurons establishes neuronal chromatin, transcriptome, and identity

AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity

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