Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Savage, Kienan I.; Gorski, Julia J.; Barros, Eliana M.; Irwin, Gareth; Manti, Lorenzo; Powell, Alexander J.; Pellagatti, Andrea; Lukashchuk, Natalia; McCance, Dennis J.; McCluggage, W. Glenn; Schettino, Giuseppe; Salto-Tellez, Manuel; Boultwood, Jacqueline; Richard, Derek J.; McDade, Simon S.; Harkin, D. Paul

doi:10.1016/j.molcel.2014.03.021

Cited by 151 publications

(186 citation statements)

References 29 publications

(37 reference statements)

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“…35 Recently, Bclaf1 was identified as a component of the RNA splicing complex and regulates the stability of cyclin D and BRCA1 mRNA. 36,37 Whether this function of Bclaf1 is related to C/EBPβ upregulation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Lee et al 24 reported that Bclaf1 interacted with γH2AX and may regulate the Ku70/DNA-PKcs complex in response to DNA damage. Savage et al 37 demonstrated that Bclaf1 complexes with BRCA1 and influences the radiosensitivity of cells. We have demonstrated that Bclaf1 is involved in persistent and mild DNA damage-induced senescence downstream of NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

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Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Sun

Geng

et al. 2016

Cell Death Differ

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Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) and C/EBPβ (CCAAT/enhancer-binding protein-β) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-κB pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-κB is essential for C/EBPβ upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBPβ and cooperate with C/EBPβ to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-κB to C/EBPβ during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-κB may determine the effectiveness of therapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Sun

Geng

et al. 2016

Cell Death Differ

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“…For example, it has been demonstrated that SRSF2 plays a critical role in maintaining genome stability (Xiao et al 2007), and recent studies also showed its direct activity in transcriptional control (Mo et al 2013). A recent study also revealed that U2AF1 and SF3B1 are part of the BRCA-DNA damage response complex (Savage et al 2014). These observations raise the possibility that mutations in these splicing factors may employ both splicing-dependent and -independent mechanisms to cause MDS.…”

Section: Discussionmentioning

confidence: 99%

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Qiu

Zhou

Thol

et al. 2016

RNA

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Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3 ′ splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS.

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“…S6B,C). In contrast, Bclaf1, which is an RS domain-containing RNA-binding protein that has been shown to associate with Brca1 upon DNA damage (Savage et al 2014), showed the opposite switch upon doxorubicin treatment. The DI in Bclaf1 was reduced by almost half, and the total transcript level as well as the coding isoform fraction were up-regulated by 4 h, while the NMD isoform was down-regulated, consistent with the DI pool contributing to increased coding message (Fig.…”

Section: Dna Damage Triggers Changes In Splicing Of a Subset Of Dismentioning

confidence: 94%

Detained introns are a novel, widespread class of post-transcriptionally spliced introns

2015

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Deep sequencing of embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within polyadenylated transcripts; we classified these as ''detained'' introns (DIs). We identified thousands of DIs, many of which are evolutionarily conserved, in human and mouse cell lines as well as the adult mouse liver. DIs can have half-lives of over an hour yet remain in the nucleus and are not subject to nonsense-mediated decay (NMD). Drug inhibition of Clk, a stress-responsive kinase, triggered rapid splicing changes for a specific subset of DIs; half showed increased splicing, and half showed increased intron detention, altering transcript pools of >300 genes. Srsf4, which undergoes a dramatic phosphorylation shift in response to Clk kinase inhibition, regulates the splicing of some DIs, particularly in genes encoding RNA processing and splicing factors. The splicing of some DIs-including those in Mdm4, a negative regulator of p53-was also altered following DNA damage. After 4 h of Clk inhibition, the expression of >400 genes changed significantly, and almost one-third of these are p53 transcriptional targets. These data suggest a widespread mechanism by which the rate of splicing of DIs contributes to the level of gene expression.

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Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability

Cited by 151 publications

References 29 publications

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Detained introns are a novel, widespread class of post-transcriptionally spliced introns

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