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TERRA

Mammalian telomeres are bound by a ribonucleoprotein cap consisting of the protein complex shelterin, and the telomere repeat containing RNA, TERRA. TERRA knockdown induces telomere dysfunction and instability. However, relatively little is known about how TERRA functions either on, or independent of, telomeric chromatin. One of the goals of our research is to gain detailed mechanistic insight towards TERRA function.

 
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Alternative Lengthening of Telomeres

Cancer cells overcome the replicative senescence associated with critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme telomerase, or activation of the Alternative Lengthening of Telomeres (ALT) pathway, account for cellular immortalization in approximately 95% of all human cancers. While the molecular mechanisms leading to activation of these pathways has not been fully elucidated, improperly capped telomeres are believed to be an early event in the process. Our lab is interested in not only understanding how ALT arises, but also how ALT is maintained in cancer. The goal of these studies will be to identify tractable targets in the treatment of ALT positive cancers including, osteosarcoma and glioblastoma.

 
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ncRNA

RNA provides the framework for the assembly of some of the most intricate macromolecular complexes within the cell, including the spliceosome and the mature ribosome. The assembly of these complexes relies on the coordinated association of RNA with hundreds of trans-acting protein factors. While some of these trans-acting factors are RNA-binding proteins (RBPs), others are adaptor proteins, and others still, function as both. Defects in the assembly of these complexes results in a number of human pathologies including neurodegeneration and cancer. Here, we demonstrate that Silencing Defective 2 (SDE2) is both an RNA binding protein and also a trans-acting adaptor protein that functions to regulate RNA splicing and ribosome biogenesis. SDE2 depletion leads to widespread changes in alternative splicing, defects in ribosome biogenesis and ultimately complete loss of cell viability. Our data highlight SDE2 as a previously uncharacterized essential gene required for the assembly and maturation of the complexes that carry out two of the most fundamental processes in mammalian cells.

 

  • PUBLICATIONS

    1.Floro J, Dai A, Metzger A, Mora-Martin A, Ganem NJ, Cifuentes D, Wu CS, Dalal J, Lyons SM, Labadorf A, Flynn RL. SDE2 is an essential gene required for ribosome biogenesis and the regulation of alternative splicing. Nucleic Acids Res. 2021 Aug 07. PMID: 34365507

    2. Mason-Osann E, Terranova K, Lupo N, Lock YJ, Carson LM, Flynn RL. RAD54 promotes alternative lengthening of telomeres by mediating branch migration. EMBO Rep. 2020 06 04; 21(6):e49495. PMID: 32337843; PMCID: PMC7271314; DOI: 10.15252/embr.201949495;

    3. Flynn RL, Heaphy CM. Surviving Telomere Attrition with the MiDAS Touch. Trends Genet. 2019 11; 35(11):783-785. PMID: 31526614

    4. Panier S, Maric M, Hewitt G, Mason-Osann E, Gali H, Dai A, Labadorf A, Guervilly JH, Ruis P, Segura-Bayona S, Belan O, Marzec P, Gaillard PHL, Flynn RL, Boulton SJ. SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance. Mol Cell. 2019 10 03; 76(1):27-43.e11. PMID: 31447390; PMCID: PMC6863466; DOI: 10.1016/j.molcel.2019.07.010;

    5. Mason-Osann E, Gali H, Flynn RL. Resolving Roadblocks to Telomere Replication. Methods Mol Biol. 2019; 1999:31-57. PMID: 31127568

    6. Gali H, Mason-Osann E, Flynn RL. Direct Visualization of DNA Replication at Telomeres Using DNA Fiber Combing Combined with Telomere FISH. Methods Mol Biol. 2019; 1999:319-325. PMID: 31127588

    7. Mason-Osann E, Dai A, Floro J, Lock YJ, Reiss M, Gali H, Matschulat A, Labadorf A, Flynn RL. Identification of a novel gene fusion in ALT positive osteosarcoma. Oncotarget. 2018 Aug 28; 9(67):32868-32880. PMID: 30214690; PMCID: PMC6132345; DOI: 10.18632/oncotarget.26029;

    8. Cox KE, Maréchal A, Flynn RL. SMARCAL1 Resolves Replication Stress at ALT Telomeres. Cell Rep. 2016 Feb 9; 14(5):1032-40. PMID: 26832416; PMCID: PMC5051350; DOI: 10.1016/j.celrep.2016.01.011;

    9. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suvà ML, Benes CH, Haber DA, Boussin FD, Zou L. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015 Jan 16; 347(6219):273-7. PMID: 25593184; PMCID: PMC4358324; DOI: 10.1126/science.1257216;

    10. Flynn RL, Chang S, Zou L. RPA and POT1: friends or foes at telomeres? Cell Cycle. 2012 Feb 15; 11(4):652-7. PMID: 22373525; PMCID: PMC3318101; DOI: 10.4161/cc.11.4.19061;

    11. Flynn RL, Centore RC, O'Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 2011 Mar 24; 471(7339):532-6. PMID: 21399625; PMCID: PMC3078637; DOI: 10.1038/nature09772;

    12. Flynn RL, Zou L. ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci. 2011 Mar; 36(3):133-40. PMID: 20947357; PMCID: PMC3024454; DOI: 10.1016/j.tibs.2010.09.005;

    13. Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin J, Dyson NJ, Walter JC, Zou L. CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell. 2010 Oct 8; 40(1):22-33. PMID: 20932472; PMCID: PMC2957874; DOI: 10.1016/j.molcel.2010.09.015;

    14. Flynn RL, Zou L. Oligonucleotide/oligosaccharide-binding fold proteins: a growing family of genome guardians. Crit Rev Biochem Mol Biol. 2010 Aug; 45(4):266-75. PMID: 20515430; PMCID: PMC2906097; DOI: 10.3109/10409238.2010.488216;

    15. Xie J, Litman R, Wang S, Peng M, Guillemette S, Rooney T, Cantor SB. Targeting the FANCJ-BRCA1 interaction promotes a switch from recombination to poleta-dependent bypass. Oncogene. 2010 Apr 29; 29(17):2499-508. PMID: 20173781; PMCID: PMC2909592; DOI: 10.1038/onc.2010.18

    16. Litman R, Gupta R, Brosh RM Jr, Cantor SB. BRCA-FA pathway as a target for anti-tumor drugs. Anticancer Agents Med Chem. 2008; 8(4):426-30.

    17. Peng M, Litman R, Xie J, Sharma S, Brosh RM, Cantor SB. The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J. 2007 Jul 11; 26(13):3238-49. PMID: 17581638; PMCID: PMC1914102; DOI: 10.1038/sj.emboj.7601754;

    18. Peng, M., R. Litman, Z. Jin, G. Fong and S.B. Cantor. BACH1 is a DNA repair protein supporting BRCA1 damage response. Oncogene. 2006; 25:2245-53.

    19. Litman, R., M. Peng, Z. Jin, F. Zhang, J. Zhang, S. Powell, P.R. Andreassen, and S.B. Cantor. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell. 2005; 8:255-265.

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