SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

Tsao

2016

IJMS

Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases.

Section: Impacts Of Alternative Splicing Events On Apoptosismentioning

confidence: 99%

Differential Impacts of Alternative Splicing Networks on Apoptosis

Tsao

2016

IJMS

“…Indeed, each major splicing factor mutation has been demonstrated to alter a large number of splicing events in cellular and animal models (Kim et al, 2015; Komeno et al, 2015; Kon et al, 2017; Obeng et al, 2016; Shirai et al, 2015; Wang et al, 2016). In particular, disease development has been functionally linked to the inclusion of a “toxic” exon in the Ezh2 gene in Srsf2 (P95H) knockin mice (Kim et al, 2015) and a polyadenylation switch event in the autophagy gene Atg7 caused by U2af1 (S34F) overexpression on a murine pro-B cell model (Park et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations

et al. 2018

Self Cite

SUMMARY Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway. We further demonstrate that enhanced R-loops, opposite to the expectation from gained RNA binding with mutant SRSF2, result from impaired transcription pause release because the mutant protein loses its ability to extract the RNA polymerase II (Pol II) C-terminal domain (CTD) kinase—the positive transcription elongation factor complex (P-TEFb)—from the 7SK complex. Enhanced R-loops are linked to compromised proliferation of bone-marrow-derived blood progenitors, which can be partially rescued by RNase H overexpression, suggesting a direct contribution of augmented R-loops to the MDS phenotype.

“…In consequence, mice with a heterozygous Srsf2P95H mutant develop a cytopenia by myelodysplasia whereas a homozygous Srsf2 knockout when induced in adults leads to cytopenia due to a decrease in hematopoietic progenitors associated with increased apoptosis mimicking a bone marrow aplasia. 96 Particularly, it has been shown that the Srsf2 P95H mutation in mice can lead to a missplicing and nonsense-mediated decay of Ezh2. 97 Knowing that SRSF2 mutations are enriched in leukemic transformation of MPNs (19% of the cases), this further establishes that EZH2 and the PRC2 complex are important factors in the development of MF and progression toward leukemia.…”

mentioning

confidence: 99%

Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms

Vainchenker

Královics

2017

Blood

503

530

The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.