Showing papers by "Kotb Abdelmohsen published in 2015"
TL;DR: A role is suggested for the lncRNA DDSR1 in modulating DNA repair by HR, which is induced upon DNA damage and interacts with BRCA1 and hnRNPUL1, an RNA‐binding protein involved in DNA end resection.
Abstract: Long non-coding RNAs (lncRNAs) are important players in diverse biological processes. Upon DNA damage, cells activate a complex signaling cascade referred to as the DNA damage response (DDR). Using a microarray screen, we identify here a novel lncRNA, DDSR1 (DNA damage-sensitive RNA1), which is induced upon DNA damage. DDSR1 induction is triggered in an ATM-NF-κB pathway-dependent manner by several DNA double-strand break (DSB) agents. Loss of DDSR1 impairs cell proliferation and DDR signaling and reduces DNA repair capacity by homologous recombination (HR). The HR defect in the absence of DDSR1 is marked by aberrant accumulation of BRCA1 and RAP80 at DSB sites. In line with a role in regulating HR, DDSR1 interacts with BRCA1 and hnRNPUL1, an RNA-binding protein involved in DNA end resection. Our results suggest a role for the lncRNA DDSR1 in modulating DNA repair by HR.
107 citations
04 Nov 2015
TL;DR: This study has documented systematically circRNAs expressed in skeletal muscle and has identifiedcircRNAs differentially abundant with advancing muscle age, and proposed that some of these circ RNAs might influence muscle function.
Abstract: Circular RNAs (circRNAs) have been identified in numerous species, including human, mouse, nematode, and coelacanth. They are believed to function as regulators of gene expression at least in part by sponging microRNAs. Here, we describe the identification of circRNAs in monkey (Rhesus macaque) skeletal muscle. RNA sequencing analysis was employed to identify and annotate ~12,000 circRNAs, including numerous circular intronic RNAs (ciRNAs), from skeletal muscle of monkeys of a range of ages. Reverse transcription followed by real-time quantitative (q)PCR analysis verified the presence of these circRNAs, including the existence of several highly abundant circRNAs, and the differential abundance of a subset of circRNAs as a function of age. Taken together, our study has documented systematically circRNAs expressed in skeletal muscle and has identified circRNAs differentially abundant with advancing muscle age. We propose that some of these circRNAs might influence muscle function.
93 citations
TL;DR: Comparison of microRNA expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblast cells, and suggests that the age-associated mi R-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age.
Abstract: The myogenic capacity of myoblasts decreases in skeletal muscle with age. In addition to environmental factors, intrinsic factors are important for maintaining the regenerative potential of muscle progenitor cells, but their identities are largely unknown. Here, comparative analysis of microRNA (miRNA) expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblasts. Importantly, elevating miR-431 improved the myogenic capacity of old myoblasts, while inhibiting endogenous miR-431 lowered myogenesis. Bioinformatic and biochemical analyses revealed that miR-431 directly interacted with the 3′ untranslated region (UTR) of Smad4 mRNA, which encodes one of the downstream effectors of TGF-β signaling. In keeping with the low levels of miR-431 in old myoblasts, SMAD4 levels increased in this myoblast population. Interestingly, in an in vivo model of muscle regeneration following cardiotoxin injury, ectopic miR-431 injection greatly improved muscle regeneration and reduced SMAD4 levels. Consistent with the finding that the mouse miR-431 seed sequence in the Smad4 3′ UTR is conserved in the human SMAD4 3′ UTR, inhibition of miR-431 also repressed the myogenic capacity of human skeletal myoblasts. Taken together, our results suggest that the age-associated miR-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age.
84 citations
TL;DR: The regulatory ncRNAs (primarily microRNAs and lncRNAs) identified to‐date as key modulators of senescence are reviewed and the major senescent pathways (p53/p21 and pRB/p16) are highlighted.
Abstract: Senescent cells accumulate in normal tissues with advancing age and arise by long-term culture of primary cells. Senescence develops following exposure to a range of stress-causing agents and broadly influences the physiology and pathology of tissues, organs, and systems in the body. While many proteins are known to control senescence, numerous noncoding (nc)RNAs are also found to promote or repress the senescent phenotype. Here, we review the regulatory ncRNAs (primarily microRNAs and lncRNAs) identified to-date as key modulators of senescence. We highlight the major senescent pathways (p53/p21 and pRB/p16), as well as the senescence-associated secretory phenotype (SASP) and other senescence-associated events governed by ncRNAs, and discuss the importance of understanding comprehensively the ncRNAs implicated in cell senescence.
67 citations
TL;DR: It is confirmed that the conserved RNA-binding protein Musashi1 has a preference for UAG sequences contained in a particular structural context, especially in 3′ untranslated regions, which indicates potentially new roles for MSI1 in glioblastoma.
Abstract: The conserved RNA-binding protein Musashi1 (MSI1) has emerged as a key oncogenic factor in numerous solid tumors, including glioblastoma. However, its mechanism of action has not yet been established comprehensively. To identify its target genes comprehensively and determine the main routes by which it influences glioblastoma phenotypes, we conducted individual-nucleotide resolution cross-linking and immunoprecipitation (iCLIP) experiments. We confirmed that MSI1 has a preference for UAG sequences contained in a particular structural context, especially in 3' untranslated regions. Although numerous binding sites were also identified in intronic sequences, our RNA transcriptome sequencing analysis does not favor the idea that MSI1 is a major regulator of splicing in glioblastoma cells. MSI1 target mRNAs encode proteins that function in multiple pathways of cell proliferation and cell adhesion. Since these associations indicate potentially new roles for MSI1, we investigated its impact on glioblastoma cell adhesion, morphology, migration, and invasion. These processes are known to underpin the spread and relapse of glioblastoma, in contrast to other tumors where metastasis is the main driver of recurrence and progression.
47 citations
TL;DR: It is demonstrated that a non-telomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity and suggests a pivotal role for TRF1-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release.
Abstract: The molecular mechanisms regulating axonal mRNA transport are only partially understood. Here, Zhang et al. show a nontelomeric TRF2 splice variant interacts with FMRP to regulate the transport of several axonal mRNAs involved in axonal elongation and neurotransmitter release.
37 citations
TL;DR: These findings uncover a novel mechanism by which AUF1 binding and transfer of microRNA let-7 to AGO2 facilitatesLet-7-elicited gene silencing.
Abstract: Eukaryotic gene expression is tightly regulated post-transcriptionally by RNA-binding proteins (RBPs) and microRNAs. The RBP AU-rich-binding factor 1 (AUF1) isoform p37 was found to have high affinity for the microRNA let-7b in vitro (Kd = ∼ 6 nM) in cells. Ribonucleoprotein immunoprecipitation, in vitro association, and single-molecule-binding analyses revealed that AUF1 promoted let-7b loading onto Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex (RISC). In turn, AGO2-let-7 triggered target mRNA decay. Our findings uncover a novel mechanism by which AUF1 binding and transfer of microRNA let-7 to AGO2 facilitates let-7-elicited gene silencing.
37 citations
TL;DR: It is proposed that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation, and exposure to CoCl2 increases the interaction of HuR with V EGFA mRNA and promoted the colocalization ofHuR and the distal part of the VEG FA 3′-untranslated region (UTR) in the cytoplasm.
Abstract: Vascular endothelial growth factor (VEGF) A is a master regulator of neovascularization and angiogenesis. VEGFA is potently induced by hypoxia and by pathological conditions including diabetic retinopathy and tumorigenesis. Fine-tuning of VEGFA expression by different stimuli is important for maintaining tissue vascularization and organ homeostasis. Here, we tested the effect of the hypoxia mimetic cobalt chloride (CoCl2) on VEGFA expression in human cervical carcinoma HeLa cells. We found that CoCl2 increased the levels of VEGFA mRNA and VEGFA protein without affecting VEGFA mRNA stability. Biotin pulldown analysis to capture the RNA-binding proteins (RBPs) bound to VEGFA mRNA followed by mass spectrometry analysis revealed that the RBP HuR [human antigen R, a member of the embryonic lethal abnormal vision (ELAV) family of proteins], interacts with VEGFA mRNA. VEGFA mRNA-tagging experiments showed that exposure to CoCl2 increases the interaction of HuR with VEGFA mRNA and promoted the colocalization of HuR and the distal part of the VEGFA 3'-untranslated region (UTR) in the cytoplasm. We propose that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation.
30 citations
TL;DR: These results identified β2-AR as a novel potential target for melanoma management, and (R,R')-MNF as an efficient trigger of anti-tumorigenic cAMP/PKA-dependent signaling in β 2-AR-expressing lesions.
22 citations