Mud2 functions in transcription by recruiting the Prp19 and TREX complexes to transcribed genes

Minocha, Rashmi; Popova, V. V.; Копытова, Д. В.; Misiak, Danny; Hüttelmaier, Stefan; Георгиева, С. Г.; Sträßer, Katja

doi:10.1093/nar/gky640

Cited by 18 publications

(24 citation statements)

References 74 publications

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“…In Saccharomyces cerevisiae , SYF1 interacts with THO complex and also mediates the interaction of Prp19 complex with RNA polymerase II via its C terminal domain, thus is recruited to transcribed genes linking transcription to mRNP formation. SYF1 mutation causes lower mRNA levels in vivo and impairs transcription in vitro, indicating that SYF1 is necessary for efficient transcription (41,42). In addition, our previous work showed that XAB2 deficiency results in mitotic cell cycle arrest by transcriptional regulation of CENPE (31), however, detailed mechanism on transcription regulation by XAB2 is still unknown.…”

Section: Introductionmentioning

confidence: 99%

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

Hou

et al. 2019

Nucleic Acids Research

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XAB2 is a multi-functional protein participating processes including transcription, splicing, DNA repair and mRNA export. Here, we report POLR2A, the largest catalytic subunit of RNA polymerase II, as a major target gene down-regulated after XAB2 depletion. XAB2 depletion led to severe splicing defects of POLR2A with significant intron retention. Such defects resulted in substantial loss of POLR2A at RNA and protein levels, which further impaired global transcription. Treatment of splicing inhibitor madrasin induced similar reduction of POLR2A. Screen using TMT-based quantitative proteomics identified several proteins involved in mRNA surveillance including Dom34 with elevated expression. Inhibition of translation or depletion of Dom34 rescued the expression of POLR2A by stabilizing its mRNA. Immuno-precipitation further confirmed that XAB2 associated with spliceosome components important to POLR2A expression. Domain mapping revealed that TPR motifs 2–4 and 11 of XAB2 were critical for POLR2A expression by interacting with SNW1. Finally, we showed POLR2A mediated cell senescence caused by XAB2 deficiency. Depletion of XAB2 or POLR2A induced cell senescence by up-regulation of p53 and p21, re-expression of POLR2A after XAB2 depletion alleviated cellular senescence. These data together support that XAB2 serves as a guardian of POLR2A expression to ensure global gene expression and antagonize cell senescence.

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Section: Introductionmentioning

confidence: 99%

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

Hou

et al. 2019

Nucleic Acids Research

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“…The relationship between CDC5L and some neurodegenerative and neuroimmune diseases is established in plenty researches, most of which operate with transcriptome analysis [23,24,25]. Adverse regulation of mRNA splicing in cerebral cortex through, inter alia, malfunction of CDC5L lead to a decrease of proliferative activity and disruption of the neuronal differentiation [26].…”

Section: Discussionmentioning

confidence: 99%

Perinatal changes in plasma of type 2 diabetes mellitus pregnancies who delivered newborns with cardiomyopathy, depression of the central nervous system, or hepatomegaly

Kopylov

Папышева

Gribova³

et al. 2020

Preprint

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Background Maternal diabetes either pregestational or gestational is the main risk factor contributing in development of diabetic fetopathy (DF) in newborns. There are no generalized signs of DF up to late gestational age due to insufficient sensitivity of the currently employed instrumental methods for diagnosis. Methods This is a cross-sectional prospective controlled study. Here, we reported proteomic investigation for several cases of severe types of diabetic fetopathy (cardiomyopathy (CRDM, n = 37), central nervous system depression (CNSD, n = 35) and hepatomegaly (HPMG, n = 35)) diagnosed during 30–35 gestational weeks and confirmed upon delivery by from patients with type 2 diabetes mellitus (T2DM). Control groups were comprised from women in whom T2DM had been ruled out (n = 40) and group of pregnancies with T2DM who delivered healthy newborns (n = 40). Results We found a composition of serum-based non-trivial markers capable that are strongly associated with the certain type of fetopathy or anatomical malfunctions in the affected newborns. Significant impact on mRNA splicing and DNA reparation has been determined by emerging alterations in CDCL5. Patients of CNSD groups were characterized by utmost depletion (ca. 7% of baseline) of DFP3 neurotrophic factor needed for the proper specialization of cardiomyocytes and oligodendrocytes. Corrupted regulation of non-canonical Wnt-signaling guided by PEDF (in CNSD and HPMG groups) and DAAM2 (in CRDM and HPMG groups) was also proposed. In addition, deficiency in retinoic acid and thyroxine transport was revealed by dramatic increase of TTHY in CNDS group. Conclusions We examined peripheral blood plasma and determined a small proportion of proteins indicating the pre-existing signs of DF. Most of the examined markers are participants of critical processes at different stages of embryogenesis and regulate various phases of morphogenesis. There are proteins regulating splicing and DNA repair, differentiation of neurons and their switching to the post-mitotic state. Therefore, reconstruction of the molecular interplay between the defined in proteins is decisive to appreciate cryptic violations in fetal development on the background of diabetic conditions

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“…Splicing has been proposed to be a checkpoint for Pol II pausing because splicing inhibition can lead to an increase in Pol II ChIP signal over introns, further supporting communication between the two machines ( Alexander et al 2010 ; Chathoth et al 2014 ). More recently, splicing factors, such as Mud2 and Npl3, have also been suggested to act in transcription elongation ( Dermody et al 2008 ; Minocha et al 2018 ). Nevertheless, the molecular mechanism by which Mud2 or Npl3 contributes to efficient elongation remains unknown.…”

Section: Co-transcriptional Assembly Of the Spliceosomementioning

confidence: 99%

Pre-mRNA Splicing in the Nuclear Landscape

Carrocci

Neugebauer

2019

Cold Spring Harb Symp Quant Biol

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Eukaryotic gene expression requires the cumulative activity of multiple molecular machines to synthesize and process newly transcribed pre-messenger RNA. Introns, the noncoding regions in pre-mRNA, must be removed by the spliceosome, which assembles on the pre-mRNA as it is transcribed by RNA polymerase II (Pol II). The assembly and activity of the spliceosome can be modulated by features including the speed of transcription elongation, chromatin, post-translational modifications of Pol II and histone tails, and other RNA processing events like 5′-end capping. Here, we review recent work that has revealed cooperation and coordination among co-transcriptional processing events and speculate on new avenues of research. We anticipate new mechanistic insights capable of unraveling the relative contribution of coupled processing to gene expression.

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Mud2 functions in transcription by recruiting the Prp19 and TREX complexes to transcribed genes

Cited by 18 publications

References 74 publications

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence

Perinatal changes in plasma of type 2 diabetes mellitus pregnancies who delivered newborns with cardiomyopathy, depression of the central nervous system, or hepatomegaly

Pre-mRNA Splicing in the Nuclear Landscape

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