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      Nuclear Speckle-related Protein 70 Binds to Serine/Arginine-rich Splicing Factors 1 and 2 via an Arginine/Serine-like Region and Counteracts Their Alternative Splicing Activity.

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          Abstract

          Nuclear speckles are subnuclear storage sites containing pre-mRNA splicing machinery. Proteins assembled in nuclear speckles are known to modulate transcription and pre-mRNA processing. We have previously identified nuclear speckle-related protein 70 (NSrp70) as a novel serine/arginine (SR)-related protein that co-localizes with classical SR proteins such as serine/arginine-rich splicing factor 1 (SRSF1 or ASF/SF2) and SRSF2 (SC35). NSrp70 mediates alternative splice site selection, targeting several pre-mRNAs, including CD44 exon v5. Here we demonstrated that NSrp70 interacts physically with two SR proteins, SRSF1 and SRSF2, and reverses their splicing activity in terms of CD44 exon v5 as exon exclusion. The NSrp70 RS-like region was subdivided into three areas. Deletion of the first arginine/serine-rich-like region (RS1) completely abrogated binding to the SR proteins and to target mRNA and also failed to induce splicing of CD44 exon v5, suggesting that RS1 is critical for NSrp70 functioning. Interestingly, RS1 deletion also resulted in the loss of NSrp70 and SR protein speckle positioning, implying a potential scaffolding role for NSrp70 in nuclear speckles. NSrp70 contains an N-terminal coiled-coil domain that is critical not only for self-oligomerization but also for splicing activity. Consistently, deletion of the coiled-coil domain resulted in indefinite formation of nuclear speckles. Collectively, these results demonstrate that NSrp70 acts as a new molecular counterpart for alternative splicing of target RNA, counteracting SRSF1 and SRSF2 splicing activity.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1083-351X
          0021-9258
          Mar 18 2016
          : 291
          : 12
          Affiliations
          [1 ] From the School of Life Sciences, Immune Synapse Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.
          [2 ] the Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseng-gu, Daejeon 3414, Korea, and.
          [3 ] the Academy of Immunology and Microbiology, Institute for Basic Science, and Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
          [4 ] From the School of Life Sciences, Immune Synapse Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, cdjun@gist.ac.kr.
          Article
          M115.689414
          10.1074/jbc.M115.689414
          4813587
          26797131
          8c82184d-ca08-4a5b-aa45-a33e6980f3b7
          History

          coiled-coil domain,nuclear speckle,heterogeneous nuclear ribonucleoprotein (hnRNP),dimerization,alternative splicing,SR protein,RS-like region,RNA binding protein,NSrp70,CD44

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