Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence

被引:70
作者
Maicher, Andre [1 ]
Kastner, Lisa [1 ]
Dees, Martina [1 ]
Luke, Brian [1 ]
机构
[1] Univ Heidelberg, Zentrum Mol Biol, DKFZ ZMBH Allianz, D-69120 Heidelberg, Germany
关键词
REPEAT-CONTAINING RNA; R-LOOP FORMATION; SACCHAROMYCES-CEREVISIAE; GENOMIC INSTABILITY; FORK PROGRESSION; HOMOLOGOUS RECOMBINATION; MAMMALIAN TELOMERES; YEAST TELOMERES; POLYMERASE-II; DNA;
D O I
10.1093/nar/gks358
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2 delta cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.
引用
收藏
页码:6649 / 6659
页数:11
相关论文
共 49 条
  • [1] A two-step model for senescence triggered by a single critically short telomere
    Abdallah, Pauline
    Luciano, Pierre
    Runge, Kurt W.
    Lisby, Michael
    Geli, Vincent
    Gilson, Eric
    Teixeira, M. Teresa
    [J]. NATURE CELL BIOLOGY, 2009, 11 (08) : 988 - U174
  • [2] The connection between transcription and genomic instability
    Aguilera, A
    [J]. EMBO JOURNAL, 2002, 21 (03) : 195 - 201
  • [3] Genome instability:: a mechanistic view of its causes and consequences
    Aguilera, Andres
    Gomez-Gonzalez, Belen
    [J]. NATURE REVIEWS GENETICS, 2008, 9 (03) : 204 - 217
  • [4] Transcription regulates telomere dynamics in human cancer cells
    Arora, Rajika
    Brun, Catherine M.
    Azzalin, Claus M.
    [J]. RNA, 2012, 18 (04) : 684 - 693
  • [5] Highly Transcribed RNA Polymerase II Genes Are Impediments to Replication Fork Progression in Saccharomyces cerevisiae
    Azvolinsky, Anna
    Giresi, Paul G.
    Lieb, Jason D.
    Zakian, Virginia A.
    [J]. MOLECULAR CELL, 2009, 34 (06) : 722 - 734
  • [6] Telomeres - The silence is broken
    Azzalin, Claus M.
    Lingner, Joachim
    [J]. CELL CYCLE, 2008, 7 (09) : 1161 - 1165
  • [7] Telomeric repeat-containing RNA and RNA surveillance factors at mammalian chromosome ends
    Azzalin, Claus M.
    Reichenbach, Patrick
    Khoriauli, Lela
    Giulotto, Elena
    Lingner, Joachim
    [J]. SCIENCE, 2007, 318 (5851) : 798 - 801
  • [8] The telomeric transcriptome of Schizosaccharomyces pombe
    Bah, Amadou
    Wischnewski, Harry
    Shchepachev, Vadim
    Azzalin, Claus M.
    [J]. NUCLEIC ACIDS RESEARCH, 2012, 40 (07) : 2995 - 3005
  • [9] Mechanisms and implications of transcription blockage by guanine-rich DNA sequences
    Belotserkovskii, Boris P.
    Liu, Richard
    Tornaletti, Silvia
    Krasilnikova, Maria M.
    Mirkin, Sergei M.
    Hanawalt, Philip C.
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (29) : 12816 - 12821
  • [10] Chang H.-Y., 2011, G3, V3, P197