DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?

被引:257
作者
Passos, Joao F. [1 ,2 ]
Saretzki, Gabriele [1 ,3 ]
von Zglinicki, Thomas [1 ,2 ]
机构
[1] Univ Newcastle, Inst Ageing & Hlth, Henry Wellcome Lab Biogerontol Res, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England
[2] Univ Newcastle, Ctr Integrat Syst Biol Ageing & Nutr CISBAN, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England
[3] Newcastle Univ, Inst Ageing & Hlth, Life Knowledge Pk, Crucible Lab, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
基金
英国医学研究理事会;
关键词
D O I
10.1093/nar/gkm893
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
Cellular senescence is the ultimate and irreversible loss of replicative capacity occurring in primary somatic cell culture. It is triggered as a stereotypic response to unrepaired nuclear DNA damage or to uncapped telomeres. In addition to a direct role of nuclear DNA double-strand breaks as inducer of a DNA damage response, two more subtle types of DNA damage induced by physiological levels of reactive oxygen species (ROS) can have a significant impact on cellular senescence: Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence. Improvement of mitochondrial function results in less telomeric damage and slower telomere shortening, while telomere-dependent growth arrest is associated with increased mitochondrial dysfunction. Moreover, telomerase, the enzyme complex that is known to re-elongate shortened telomeres, also appears to have functions independent of telomeres that protect against oxidative stress. Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence.
引用
收藏
页码:7505 / 7513
页数:9
相关论文
共 128 条
[1]  
Allen RG, 1999, J CELL PHYSIOL, V180, P114, DOI 10.1002/(SICI)1097-4652(199907)180:1<114::AID-JCP13>3.0.CO
[2]  
2-0
[3]   Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage [J].
Armstrong, L ;
Saretzki, G ;
Peters, H ;
Wappler, I ;
Evans, J ;
Hole, N ;
von Zglinicki, T ;
Lako, M .
STEM CELLS, 2005, 23 (04) :516-529
[4]   Genes and pathways downstream of telomerase in melanoma metastasis [J].
Bagheri, Sepideh ;
Nosrati, Mehdi ;
Li, Shang ;
Fong, Sylvia ;
Torabian, Sima ;
Rangel, Javier ;
Moore, Dan H. ;
Federman, Scot ;
LaPosa, Rebecca R. ;
Baehner, Frederick L. ;
Sagebiel, Richard W. ;
Cleaver, James E. ;
Haqq, Christopher ;
Debs, Robert J. ;
Blackburn, Elizabeth H. ;
Kashani-Sabet, Mohammed .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (30) :11306-11311
[5]   Extensive allelic variation and ultrashort telomeres in senescent human cells [J].
Baird, DM ;
Rowson, J ;
Wynford-Thomas, D ;
Kipling, D .
NATURE GENETICS, 2003, 33 (02) :203-207
[6]   High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease [J].
Bender, A ;
Krishnan, KJ ;
Morris, CM ;
Taylor, GA ;
Reeve, AK ;
Perry, RH ;
Jaros, E ;
Hersheson, JS ;
Betts, J ;
Klopstock, T ;
Taylor, RW ;
Turnbull, DM .
NATURE GENETICS, 2006, 38 (05) :515-517
[7]   'To repair or not to repair -: no longer a question':: repair of mitochondrial DNA shielding against age and cancer [J].
Berneburg, Mark ;
Kamenisch, York ;
Krutmann, Jean ;
Roecken, Martin .
EXPERIMENTAL DERMATOLOGY, 2006, 15 (12) :1005-1015
[8]   Molecular manifestations and molecular determinants of telomere capping [J].
Blackburn, EH ;
Chan, S ;
Chang, J ;
Fulton, TB ;
Krauskopf, A ;
McEachern, M ;
Prescott, J ;
Roy, J ;
Smith, C ;
Wang, H .
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, 2000, 65 :253-263
[9]   Extension of life-span by introduction of telomerase into normal human cells [J].
Bodnar, AG ;
Ouellette, M ;
Frolkis, M ;
Holt, SE ;
Chiu, CP ;
Morin, GB ;
Harley, CB ;
Shay, JW ;
Lichtsteiner, S ;
Wright, WE .
SCIENCE, 1998, 279 (5349) :349-352
[10]  
BOND JA, 1994, ONCOGENE, V9, P1885