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  1. Article: Long Non-Coding RNA Generated from

    Murphy, Michael R / Ramadei, Anthony / Doymaz, Ahmet / Varriano, Sophia / Natelson, Devorah / Yu, Amy / Aktas, Sera / Mazzeo, Marie / Mazzeo, Michael / Zakusilo, George / Kleiman, Frida E

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DNA damage activated APA event ... ...

    Abstract Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DNA damage activated APA event occurs in the first intron of
    Language English
    Publishing date 2023-01-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.10.523318
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Long non-coding RNA generated from CDKN1A gene by alternative polyadenylation regulates p21 expression during DNA damage response.

    Murphy, Michael R / Ramadei, Anthony / Doymaz, Ahmet / Varriano, Sophia / Natelson, Devorah M / Yu, Amy / Aktas, Sera / Mazzeo, Marie / Mazzeo, Michael / Zakusilo, George / Kleiman, Frida E

    Nucleic acids research

    2023  Volume 51, Issue 21, Page(s) 11911–11926

    Abstract: Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DDR-activated APA event occurs in ... ...

    Abstract Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DDR-activated APA event occurs in the first intron of CDKN1A, inducing an alternate last exon-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon DNA Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high-throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform under non-stress conditions, and SPUD is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53. The RNA binding protein HuR binds to and promotes the stability of SPUD precursor RNA. SPUD induction increases p21 protein, but not mRNA levels, affecting p21 functions in cell-cycle, CDK2 expression and cell growth. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD alters their association with CDKN1A full-length in a DDR-dependent manner, promoting CDKN1A translation. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cell-cycle.
    MeSH term(s) Cell Cycle ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage ; Polyadenylation ; Protein Isoforms/genetics ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Humans ; Cell Line, Tumor
    Chemical Substances CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; Protein Isoforms ; RNA, Long Noncoding ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2023-11-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad899
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer.

    Ghosh, Jayashri / Schultz, Bryant M / Chan, Joe / Wultsch, Claudia / Singh, Rajveer / Shureiqi, Imad / Chow, Stephanie / Doymaz, Ahmet / Varriano, Sophia / Driscoll, Melissa / Muse, Jennifer / Kleiman, Frida E / Krampis, Konstantinos / Issa, Jean-Pierre J / Sapienza, Carmen

    Cancer prevention research (Philadelphia, Pa.)

    2022  Volume 15, Issue 11, Page(s) 755–766

    Abstract: Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in ... ...

    Abstract Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as "Outlier Methylation Phenotype" (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.
    Prevention relevance: Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.
    MeSH term(s) Humans ; Epigenome ; Dysbiosis/complications ; Dysbiosis/genetics ; Dysbiosis/metabolism ; RNA, Ribosomal, 16S/genetics ; DNA Methylation ; Epigenesis, Genetic ; Intestinal Mucosa/pathology ; Colorectal Neoplasms/pathology
    Chemical Substances RNA, Ribosomal, 16S
    Language English
    Publishing date 2022-10-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2434717-6
    ISSN 1940-6215 ; 1940-6207
    ISSN (online) 1940-6215
    ISSN 1940-6207
    DOI 10.1158/1940-6207.CAPR-22-0258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: mRNA Processing Factor CstF-50 and Ubiquitin Escort Factor p97 Are BRCA1/BARD1 Cofactors Involved in Chromatin Remodeling during the DNA Damage Response.

    Fonseca, Danae / Baquero, Jorge / Murphy, Michael R / Aruggoda, Gamage / Varriano, Sophia / Sapienza, Carmen / Mashadova, Oksana / Rahman, Shadaqur / Kleiman, Frida E

    Molecular and cellular biology

    2018  Volume 38, Issue 4

    Abstract: The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) ...

    Abstract The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, facilitating chromatin remodeling during the DNA damage response (DDR). CstF-50 and p97 formed complexes with BRCA1/BARD1, Ub, and some BRCA1/BARD1 substrates, such as RNA polymerase (RNAP) II and histones. Furthermore, CstF-50 and p97 had an additive effect on the activation of the ubiquitination of these BRCA1/BARD1 substrates during DDR. Importantly, as a result of these functional interactions, BRCA1/BARD1/CstF-50/p97 had a specific effect on the chromatin structure of genes that were differentially expressed. This study provides new insights into the roles of RNA processing, BRCA1/BARD1, the Ub pathway, and chromatin structure during DDR.
    MeSH term(s) Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; Chromatin Assembly and Disassembly ; Cleavage Stimulation Factor/genetics ; Cleavage Stimulation Factor/metabolism ; DNA Damage ; DNA Repair ; DNA-Binding Proteins/metabolism ; Histones/genetics ; Histones/metabolism ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; mRNA Cleavage and Polyadenylation Factors/metabolism
    Chemical Substances BRCA1 Protein ; BRCA1 protein, human ; Cleavage Stimulation Factor ; DNA-Binding Proteins ; Histones ; Nuclear Proteins ; RNA, Messenger ; Tumor Suppressor Proteins ; Ubiquitin ; mRNA Cleavage and Polyadenylation Factors ; BARD1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; RNA Polymerase II (EC 2.7.7.-) ; Adenosine Triphosphatases (EC 3.6.1.-) ; p97 ATPase (EC 3.6.1.-)
    Language English
    Publishing date 2018-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00364-17
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1666: Show issues Location:
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  5. Article ; Online: mRNA Processing Factor CstF-50 and Ubiquitin Escort Factor p97 Are BRCA1/BARD1 Cofactors Involved in Chromatin Remodeling during the DNA Damage Response

    Fonseca, Danae / Baquero, Jorge / Murphy, Michael R. / Aruggoda, Gamage / Varriano, Sophia / Sapienza, Carmen / Mashadova, Oksana / Rahman, Shadaqur / Kleiman, Frida E.

    Molecular and Cellular Biology. 2018 Feb. 1, v. 38, no. 4 p.e00364-17-

    2018  

    Abstract: The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) ...

    Abstract The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, facilitating chromatin remodeling during the DNA damage response (DDR). CstF-50 and p97 formed complexes with BRCA1/BARD1, Ub, and some BRCA1/BARD1 substrates, such as RNA polymerase (RNAP) II and histones. Furthermore, CstF-50 and p97 had an additive effect on the activation of the ubiquitination of these BRCA1/BARD1 substrates during DDR. Importantly, as a result of these functional interactions, BRCA1/BARD1/CstF-50/p97 had a specific effect on the chromatin structure of genes that were differentially expressed. This study provides new insights into the roles of RNA processing, BRCA1/BARD1, the Ub pathway, and chromatin structure during DDR.
    Keywords DNA damage ; DNA-directed RNA polymerase ; RNA ; additive effect ; chromatin ; histones ; ligases ; ubiquitin ; ubiquitination ; BRCA1/BARD1 ; CstF-50 ; DNA damage response ; RNA polymerase II ; chromatin remodeling ; p97
    Language English
    Dates of publication 2018-0201
    Publishing place Taylor & Francis
    Document type Article ; Online
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00364-17
    Database NAL-Catalogue (AGRICOLA)

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  6. Article: Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression.

    Baquero, Jorge / Varriano, Sophia / Ordonez, Martha / Kuczaj, Pawel / Murphy, Michael R / Aruggoda, Gamage / Lundine, Devon / Morozova, Viktoriya / Makki, Ali Elhadi / Alonso, Alejandra Del C / Kleiman, Frida E

    Frontiers in molecular neuroscience

    2019  Volume 12, Page(s) 242

    Abstract: While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor ...

    Abstract While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor suppressor p53 and poly(A)-specific ribonuclease (PARN) deadenylase. Tau induces PARN activity in different cellular models during DDR, and this activation is further increased by p53 and inhibited by tau phosphorylation at residues implicated in neurological disorders. Tau's binding factor Pin1, a mitotic regulator overexpressed in cancer and depleted in Alzheimer's disease (AD), also plays a role in the activation of nuclear deadenylation. Tau, Pin1 and PARN target the expression of mRNAs deregulated in AD and/or cancer. Our findings identify novel biological roles of tau and toxic effects of hyperphosphorylated-tau. We propose a model in which factors involved in cancer and AD regulate gene expression by interactions with the mRNA processing machinery, affecting the transcriptome and suggesting insights into alternative mechanisms for the initiation and/or developments of these diseases.
    Language English
    Publishing date 2019-10-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2019.00242
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Na(+) /H(+) exchanger 1 (NHE1) function is necessary for maintaining mammary tissue architecture.

    Jenkins, Edmund C / Debnath, Shawon / Varriano, Sophia / Gundry, Stephen / Fata, Jimmie E

    Developmental dynamics : an official publication of the American Association of Anatomists

    2014  Volume 243, Issue 2, Page(s) 229–242

    Abstract: Background: The mammary gland is an ideal model to study the link between form and function in normal tissue. Perhaps as interesting as the cues necessary to generate this structure are the signals required to maintain its branched architecture over the ...

    Abstract Background: The mammary gland is an ideal model to study the link between form and function in normal tissue. Perhaps as interesting as the cues necessary to generate this structure are the signals required to maintain its branched architecture over the lifetime of the organism, since likely these pathways are de-regulated in malignancies. Previously, we have shown that the Na(+) /H(+) exchanger 1 (NHE1), a critical regulator of intracellular pH, was necessary for mammary branching morphogenesis. Here we provide strong evidence that NHE1 function is also necessary for maintaining mammary branched architecture.
    Results: Inhibition of NHE1 with 5-N-Methy-N-isobutyl amiloride (MIA) on branched structures resulted in a rapid (within 24 hr) and reversible loss of branched architecture that was not accompanied by any overt changes in cell proliferation or cell death. NHE1 inhibition led to a significant acidification of intracellular pH in the branched end buds that preceded a number of events, including altered tissue polarity of myoepithelial cells, loss of NHE1 basal polarity, F-actin rearrangements, and decreased E-cadherin expression.
    Conclusions: Our results implicate NHE1 function and intracellular pH homeostasis as key factors that maintain mammary tissue architecture, thus, indirectly allowing for mammary function as a milk-providing (form) and -producing (function) gland.
    MeSH term(s) Actins/metabolism ; Amiloride/analogs & derivatives ; Amiloride/pharmacology ; Animals ; Cadherins/metabolism ; Cation Transport Proteins/antagonists & inhibitors ; Cation Transport Proteins/metabolism ; Cell Death/physiology ; Cell Polarity/physiology ; Cells, Cultured ; Female ; Hydrogen-Ion Concentration/drug effects ; Immunoblotting ; Keratins/metabolism ; Mammary Glands, Animal/anatomy & histology ; Mammary Glands, Animal/drug effects ; Mammary Glands, Animal/physiology ; Mice ; Phalloidine ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers/antagonists & inhibitors ; Sodium-Hydrogen Exchangers/metabolism ; Zonula Occludens-1 Protein/metabolism
    Chemical Substances Actins ; Cadherins ; Cation Transport Proteins ; Slc9a1 protein, mouse ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers ; Tjp1 protein, mouse ; Zonula Occludens-1 Protein ; Phalloidine (17466-45-4) ; Keratins (68238-35-7) ; Amiloride (7DZO8EB0Z3) ; 5-(N-methyl-N-isobutyl)amiloride (96861-65-3)
    Language English
    Publishing date 2014-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.24032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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