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Frontiers in Biology

ISSN 1674-7984

ISSN 1674-7992(Online)

CN 11-5892/Q

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Front. Biol.    2017, Vol. 12 Issue (1) : 49-62    https://doi.org/10.1007/s11515-016-1435-x
REVIEW
Mechanisms of genome instability in Hutchinson-Gilford progeria
Haoyue Zhang,Kan Cao()
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
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Abstract

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder. It arises from a single point mutation in the LMNA gene. This mutation stimulates an aberrant splicing event and produces progerin, an isoform of the lamin A protein. Accumulation of progerin disrupts numerous physiological pathways and induces defects in nuclear architecture, gene expression, histone modification, cell cycle regulation, mitochondrial functionality, genome integrity and much more.

OBJECTIVE: Among these phenotypes, genomic instability is tightly associated with physiological aging and considered a main contributor to the premature aging phenotypes. However, our understanding of the underlying molecular mechanisms of progerin-caused genome instability is far from clear.

RESULTS AND CONCLUSION: In this review, we summarize some of the recent findings and discuss potential mechanisms through which, progerin affects DNA damage repair and leads to genome integrity.
Keywords HGPS      DDR      DSB repair     
Corresponding Author(s): Kan Cao   
Just Accepted Date: 16 November 2016   Online First Date: 26 December 2016    Issue Date: 28 February 2017
 Cite this article:   
Haoyue Zhang,Kan Cao. Mechanisms of genome instability in Hutchinson-Gilford progeria[J]. Front. Biol., 2017, 12(1): 49-62.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-016-1435-x
https://academic.hep.com.cn/fib/EN/Y2017/V12/I1/49
Fig.1  A scheme of the classic HGPS mutation in LMNA gene. The consensus splice donor site, wild type and HGPS LMNA sequences are shown. The 1824 cysteine in the wild-type LMNA gene is mutated into a thymine in HGPS. This mutation creates a cryptic splice donor site in exon 11, which can be recognized by the spliceosome and causes an in-frame deletion of 150 nucleotides. The splicing variant will subsequently yield a mutant protein which bears a 50 amino acid shorter than wild type lamin A.
Fig.2  A scheme cell cycle dependent HR/NHEJ pathway choice in normal and HGPS cells. In normal cells: NHEJ is the predominant DSB repair pathway in G0/G1 phase. In S/G2 phase, HR becomes prevalent and antagonizes with NHEJ to limit its effect. In G0/G1 phase HGPS cells: NHEJ is significantly impaired, while HR is completely undetectable. In S/G2 phase HGPS cells: HR is significantly impaired. *: The efficiencies of NHEJ in S/G2 phase HGPS cells may vary between cell types. In S/G2 phase HGPS fibroblasts, NHEJ is similarly effective compared to normal control fibroblasts. In S/G2 phase HGPS SMCs, NHEJ is significantly more effective than that in normal control SMCs.
Fig.3  Molecular mechanisms underlying HGPS genome instability. A summary of current molecular mechanisms through which, progerin perturbs HGPS genome integrity. These mechanisms are categorized into three groups: disrupted DDR, defective DSB repair and increased source of DNA damage.
1 Ayrapetov M K, Gursoy-Yuzugullu O, Xu C, Xu Y, Price B D (2014). DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin. Proc Natl Acad Sci USA, 111(25): 9169–9174
https://doi.org/10.1073/pnas.1403565111 pmid: 24927542
2 Bakkenist C J, Kastan M B (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421(6922): 499–506
https://doi.org/10.1038/nature01368 pmid: 12556884
3 Bird A W, Yu D Y, Pray-Grant M G, Qiu Q, Harmon K E, Megee P C, Grant P A, Smith M M, Christman M F (2002). Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature, 419(6905): 411–415
https://doi.org/10.1038/nature01035 pmid: 12353039
4 Bothmer A, Robbiani D F, Feldhahn N, Gazumyan A, Nussenzweig A, Nussenzweig M C (2010). 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J Exp Med, 207(4): 855–865
https://doi.org/10.1084/jem.20100244 pmid: 20368578
5 Branzei D, Foiani M (2005). The DNA damage response during DNA replication. Curr Opin Cell Biol, 17(6): 568–575
https://doi.org/10.1016/j.ceb.2005.09.003 pmid: 16226452
6 Branzei D, Foiani M (2010). Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol, 11(3): 208–219
https://doi.org/10.1038/nrm2852 pmid: 20177396
7 Brosh R M Jr, Bellani M, Liu Y, Seidman M M (2016). Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging. Ageing Res Rev: S1568-1637(16)30081-2
pmid: 27223997
8 Bunting S F, Callén E, Wong N, Chen H T, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, Xu X, Deng C X, Finkel T, Nussenzweig M, Stark J M, Nussenzweig A (2010). 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell, 141(2): 243–254
https://doi.org/10.1016/j.cell.2010.03.012 pmid: 20362325
9 Burma S, Chen B P, Murphy M, Kurimasa A, Chen D J (2001). ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem, 276(45): 42462–42467
https://doi.org/10.1074/jbc.C100466200 pmid: 11571274
10 Cao K, Capell B C, Erdos M R, Djabali K, Collins F S (2007). A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proc Natl Acad Sci USA, 104(12): 4949–4954
https://doi.org/10.1073/pnas.0611640104 pmid: 17360355
11 Cao K, Graziotto J J, Blair C D, Mazzulli J R, Erdos M R, Krainc D, Collins F S (2011). Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med, 3(89): 89ra58
https://doi.org/10.1126/scitranslmed.3002346 pmid: 21715679
12 Capell B C, Collins F S (2006). Human laminopathies: nuclei gone genetically awry. Nat Rev Genet, 7(12): 940–952
https://doi.org/10.1038/nrg1906 pmid: 17139325
13 Capell B C, Erdos M R, Madigan J P, Fiordalisi J J, Varga R, Conneely K N, Gordon L B, Der C J, Cox A D, Collins F S (2005). Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA, 102(36): 12879–12884
https://doi.org/10.1073/pnas.0506001102 pmid: 16129833
14 Capell B C, Olive M, Erdos M R, Cao K, Faddah D A, Tavarez U L, Conneely K N, Qu X, San H, Ganesh S K, Chen X, Avallone H, Kolodgie F D, Virmani R, Nabel E G, Collins F S (2008). A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc Natl Acad Sci USA, 105(41): 15902–15907
https://doi.org/10.1073/pnas.0807840105 pmid: 18838683
15 Chapman J R, Jackson S P (2008). Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO Rep, 9(8): 795–801
https://doi.org/10.1038/embor.2008.103 pmid: 18583988
16 Chapman J R, Taylor M R, Boulton S J (2012). Playing the end game: DNA double-strand break repair pathway choice. Mol Cell, 47(4): 497–510
https://doi.org/10.1016/j.molcel.2012.07.029 pmid: 22920291
17 Chen J H, Hales C N, Ozanne S E (2007). DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res, 35(22): 7417–7428
https://doi.org/10.1093/nar/gkm681 pmid: 17913751
18 Childs B G, Baker D J, Kirkland J L, Campisi J, van Deursen J M (2014). Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep, 15(11): 1139–1153
https://doi.org/10.15252/embr.201439245 pmid: 25312810
19 Ciccia A, Elledge S J (2010). The DNA damage response: making it safe to play with knives. Mol Cell, 40(2): 179–204
https://doi.org/10.1016/j.molcel.2010.09.019 pmid: 20965415
20 Cooke M S, Evans M D, Dizdaroglu M, Lunec J (2003). Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J, 17(10): 1195–1214
https://doi.org/10.1096/fj.02-0752rev pmid: 12832285
21 d’Adda di Fagagna F (2008). Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer, 8(7): 512–522
https://doi.org/10.1038/nrc2440 pmid: 18574463
22 D’Andrea A D, Grompe M (2003). The Fanconi anaemia/BRCA pathway. Nat Rev Cancer, 3(1): 23–34
https://doi.org/10.1038/nrc970 pmid: 12509764
23 Das A, Grotsky D A, Neumann M A, Kreienkamp R, Gonzalez-Suarez I, Redwood A B, Kennedy B K, Stewart C L, Gonzalo S (2013). Lamin A Dexon9 mutation leads to telomere and chromatin defects but not genomic instability. Nucleus, 4(5): 410–419
https://doi.org/10.4161/nucl.26873 pmid: 24153156
24 De Bont R, van Larebeke N (2004). Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis, 19(3): 169–185
https://doi.org/10.1093/mutage/geh025 pmid: 15123782
25 Dobbin M M, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao P C, Qiu Y, Zhao Y, Tsai L H (2013). SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci, 16(8): 1008–1015
https://doi.org/10.1038/nn.3460 pmid: 23852118
26 Eriksson M, Brown W T, Gordon L B, Glynn M W, Singer J, Scott L, Erdos M R, Robbins C M, Moses T Y, Berglund P, Dutra A, Pak E, Durkin S, Csoka A B, Boehnke M, Glover T W, Collins F S (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423(6937): 293–298
https://doi.org/10.1038/nature01629 pmid: 12714972
27 Escribano-Díaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young J T, Tkáč J, Cook M A, Rosebrock A P, Munro M, Canny M D, Xu D, Durocher D (2013). A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol Cell, 49(5): 872–883
https://doi.org/10.1016/j.molcel.2013.01.001 pmid: 23333306
28 Flynn R L, Zou L (2011). ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci, 36(3): 133–140
https://doi.org/10.1016/j.tibs.2010.09.005 pmid: 20947357
29 Fradet-Turcotte A, Canny M D, Escribano-Díaz C, Orthwein A, Leung C C, Huang H, Landry M C, Kitevski-LeBlanc J, Noordermeer S M, Sicheri F, Durocher D (2013). 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature, 499(7456): 50–54
https://doi.org/10.1038/nature12318 pmid: 23760478
30 Friedberg E C, McDaniel L D, Schultz R A (2004). The role of endogenous and exogenous DNA damage and mutagenesis. Curr Opin Genet Dev, 14(1): 5–10
https://doi.org/10.1016/j.gde.2003.11.001 pmid: 15108798
31 Garinis G A, van der Horst G T, Vijg J, Hoeijmakers J H (2008). DNA damage and ageing: new-age ideas for an age-old problem. Nat Cell Biol, 10(11): 1241–1247
https://doi.org/10.1038/ncb1108-1241 pmid: 18978832
32 Ghosh S, Liu B, Wang Y, Hao Q, Zhou Z (2015). Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair. Cell Reports, 13(7): 1396–1406
https://doi.org/10.1016/j.celrep.2015.10.006 pmid: 26549451
33 Gibbs-Seymour I, Markiewicz E, Bekker-Jensen S, Mailand N, Hutchison C J (2015). Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage. Aging Cell, 14(2): 162–169
https://doi.org/10.1111/acel.12258 pmid: 25645366
34 Goldman R D, Shumaker D K, Erdos M R, Eriksson M, Goldman A E, Gordon L B, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins F S (2004). Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA, 101(24): 8963–8968
https://doi.org/10.1073/pnas.0402943101 pmid: 15184648
35 Gonzalez-Suarez I, Redwood A B, Gonzalo S (2009). Loss of A-type lamins and genomic instability. Cell Cycle, 8(23): 3860–3865
https://doi.org/10.4161/cc.8.23.10092 pmid: 19901537
36 Gonzalez-Suarez I, Redwood A B, Grotsky D A, Neumann M A, Cheng E H, Stewart C L, Dusso A, Gonzalo S (2011). A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair. EMBO J, 30(16): 3383–3396
https://doi.org/10.1038/emboj.2011.225 pmid: 21750527
37 Gonzalo S (2014). DNA damage and lamins. Adv Exp Med Biol, 773: 377–399
https://doi.org/10.1007/978-1-4899-8032-8_17 pmid: 24563357
38 Gonzalo S, Kreienkamp R (2015). DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome. Curr Opin Cell Biol, 34: 75–83
https://doi.org/10.1016/j.ceb.2015.05.007 pmid: 26079711
39 Gonzalo S, Kreienkamp R, Askjaer P (2016). Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev: S1568-1637(16)30134-9
pmid: 27374873
40 Gordon L B, Kleinman M E, Miller D T, Neuberg D S, Giobbie-Hurder A, Gerhard-Herman M, Smoot L B, Gordon C M, Cleveland R, Snyder B D, Fligor B, Bishop W R, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich N J, Nazarian A, Liang M G, Huh S Y, Schwartzman A, Kieran M W (2012). Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA, 109(41): 16666–16671
https://doi.org/10.1073/pnas.1202529109 pmid: 23012407
41 Gordon L B, Massaro J, D’Agostino R B Sr, Campbell S E, Brazier J, Brown W T, Kleinman M E, Kieran M W, and the Progeria Clinical Trials Collaborative (2014). Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation, 130(1): 27–34
https://doi.org/10.1161/CIRCULATIONAHA.113.008285 pmid: 24795390
42 Gordon L B, McCarten K M, Giobbie-Hurder A, Machan J T, Campbell S E, Berns S D, Kieran M W (2007). Disease progression in Hutchinson-Gilford progeria syndrome: impact on growth and development. Pediatrics, 120(4): 824–833
https://doi.org/10.1542/peds.2007-1357 pmid: 17908770
43 Gupta A, Hunt C R, Chakraborty S, Pandita R K, Yordy J, Ramnarain D B, Horikoshi N, Pandita T K (2014). Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res, 181(1): 1–8
https://doi.org/10.1667/RR13572.1 pmid: 24320053
44 Haffner M C, De Marzo A M, Meeker A K, Nelson W G, Yegnasubramanian S (2011). Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin Cancer Res, 17(12): 3858–3864
https://doi.org/10.1158/1078-0432.CCR-10-2044 pmid: 21385925
45 Helleday T, Eshtad S, Nik-Zainal S (2014). Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet, 15(9): 585–598
https://doi.org/10.1038/nrg3729 pmid: 24981601
46 Hoeijmakers J H (2009). DNA damage, aging, and cancer. N Engl J Med, 361(15): 1475–1485
https://doi.org/10.1056/NEJMra0804615 pmid: 19812404
47 Kelman Z (1997). PCNA: structure, functions and interactions. Oncogene, 14(6): 629–640
https://doi.org/10.1038/sj.onc.1200886 pmid: 9038370
48 Kinner A, Wu W, Staudt C, Iliakis G (2008). Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res, 36(17): 5678–5694
https://doi.org/10.1093/nar/gkn550 pmid: 18772227
49 Kolas N K, Chapman J R, Nakada S, Ylanko J, Chahwan R, Sweeney F D, Panier S, Mendez M, Wildenhain J, Thomson T M, Pelletier L, Jackson S P, Durocher D (2007). Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science, 318(5856): 1637–1640
https://doi.org/10.1126/science.1150034 pmid: 18006705
50 Krishnan V, Chow M Z, Wang Z, Zhang L, Liu B, Liu X, Zhou Z (2011). Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci USA, 108(30): 12325–12330
https://doi.org/10.1073/pnas.1102789108 pmid: 21746928
51 Kuo L J, Yang L X (2008). Gamma-H2AX- a novel biomarker for DNA double-strand breaks. In Vivo, 22(3): 305–309
pmid: 18610740
52 Lavin M F (2008). Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol, 9(10): 759–769
https://doi.org/10.1038/nrm2514 pmid: 18813293
53 Lee J H, Paull T T (2004). Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science, 304(5667): 93–96
https://doi.org/10.1126/science.1091496 pmid: 15064416
54 Lee J H, Paull T T (2005). ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science, 308(5721): 551–554
https://doi.org/10.1126/science.1108297 pmid: 15790808
55 Lee J H, Paull T T (2007). Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene, 26(56): 7741–7748
https://doi.org/10.1038/sj.onc.1210872 pmid: 18066086
56 Li X, Corsa C A, Pan P W, Wu L, Ferguson D, Yu X, Min J, Dou Y (2010). MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Mol Cell Biol, 30(22): 5335–5347
https://doi.org/10.1128/MCB.00350-10 pmid: 20837706
57 Lin M T, Beal M F (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature, 443(7113): 787–795
https://doi.org/10.1038/nature05292 pmid: 17051205
58 Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy B K, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z (2012). Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab, 16(6): 738–750
https://doi.org/10.1016/j.cmet.2012.11.007 pmid: 23217256
59 Liu B, Wang J, Chan K M, Tjia W M, Deng W, Guan X, Huang J D, Li K M, Chau P Y, Chen D J, Pei D, Pendas A M, Cadiñanos J, López-Otín C, Tse H F, Hutchison C, Chen J, Cao Y, Cheah K S, Tryggvason K, Zhou Z (2005). Genomic instability in laminopathy-based premature aging. Nat Med, 11(7): 780–785
https://doi.org/10.1038/nm1266 pmid: 15980864
60 Liu B, Wang Z, Ghosh S, Zhou Z (2013a). Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair and accelerates senescence in progeria mouse model. Aging Cell, 12(2): 316–318
https://doi.org/10.1111/acel.12035 pmid: 23173799
61 Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z (2013b). Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun, 4: 1868
https://doi.org/10.1038/ncomms2885 pmid: 23695662
62 Liu Y, Rusinol A, Sinensky M, Wang Y, Zou Y (2006). DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J Cell Sci, 119(Pt 22): 4644–4649
https://doi.org/10.1242/jcs.03263 pmid: 17062639
63 Liu Y, Wang Y, Rusinol A E, Sinensky M S, Liu J, Shell S M, Zou Y (2008). Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A. FASEB J, 22(2): 603–611
https://doi.org/10.1096/fj.07-8598com pmid: 17848622
64 Lombard D B, Chua K F, Mostoslavsky R, Franco S, Gostissa M, Alt F W (2005). DNA repair, genome stability, and aging. Cell, 120(4): 497–512
https://doi.org/10.1016/j.cell.2005.01.028 pmid: 15734682
65 Longhese M P (2008). DNA damage response at functional and dysfunctional telomeres. Genes Dev, 22(2): 125–140
https://doi.org/10.1101/gad.1626908 pmid: 18198332
66 Mahen R, Hattori H, Lee M, Sharma P, Jeyasekharan A D, Venkitaraman A R (2013). A-type lamins maintain the positional stability of DNA damage repair foci in mammalian nuclei. PLoS One, 8(5): e61893
https://doi.org/10.1371/journal.pone.0061893 pmid: 23658700
67 Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, Lukas J (2007). RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell, 131(5): 887–900
https://doi.org/10.1016/j.cell.2007.09.040 pmid: 18001824
68 Malaquin N, Carrier-Leclerc A, Dessureault M, Rodier F (2015). DDR-mediated crosstalk between DNA-damaged cells and their microenvironment. Front Genet, 6: 94
https://doi.org/10.3389/fgene.2015.00094 pmid: 25815006
69 Manju K, Muralikrishna B, Parnaik V K (2006). Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci. J Cell Sci, 119(Pt 13): 2704–2714
https://doi.org/10.1242/jcs.03009 pmid: 16772334
70 Mathew C G (2006). Fanconi anaemia genes and susceptibility to cancer. Oncogene, 25(43): 5875–5884
https://doi.org/10.1038/sj.onc.1209878 pmid: 16998502
71 Mattiroli F, Vissers J H, van Dijk W J, Ikpa P, Citterio E, Vermeulen W, Marteijn J A, Sixma T K (2012). RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell, 150(6): 1182–1195
https://doi.org/10.1016/j.cell.2012.08.005 pmid: 22980979
72 Mazouzi A, Velimezi G, Loizou J I (2014). DNA replication stress: causes, resolution and disease. Exp Cell Res, 329(1): 85–93
https://doi.org/10.1016/j.yexcr.2014.09.030 pmid: 25281304
73 McCord R P, Nazario-Toole A, Zhang H, Chines P S, Zhan Y, Erdos M R, Collins F S, Dekker J, Cao K (2013). Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res, 23(2): 260–269
https://doi.org/10.1101/gr.138032.112 pmid: 23152449
74 Merideth M A, Gordon L B, Clauss S, Sachdev V, Smith A C, Perry M B, Brewer C C, Zalewski C, Kim H J, Solomon B, Brooks B P, Gerber L H, Turner M L, Domingo D L, Hart T C, Graf J, Reynolds J C, Gropman A, Yanovski J A, Gerhard-Herman M, Collins F S, Nabel E G, Cannon R O 3rd, Gahl W A, Introne W J (2008). Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med, 358(6): 592–604
https://doi.org/10.1056/NEJMoa0706898 pmid: 18256394
75 Mirkin E V, Mirkin S M (2007). Replication fork stalling at natural impediments. Microbiol Mol Biol Rev, 71(1): 13–35
https://doi.org/10.1128/MMBR.00030-06 pmid: 17347517
76 Moir R D, Spann T P, Herrmann H, Goldman R D (2000). Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J Cell Biol, 149(6): 1179–1192
https://doi.org/10.1083/jcb.149.6.1179 pmid: 10851016
77 Mostoslavsky R, Chua K F, Lombard D B, Pang W W, Fischer M R, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy M M, Mills K D, Patel P, Hsu J T, Hong A L, Ford E, Cheng H L, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger M O, Hursting S, Barrett J C, Guarente L, Mulligan R, Demple B, Yancopoulos G D, Alt F W (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124(2): 315–329
https://doi.org/10.1016/j.cell.2005.11.044 pmid: 16439206
78 Murphy M P (2009). How mitochondria produce reactive oxygen species. Biochem J, 417(1): 1–13
https://doi.org/10.1042/BJ20081386 pmid: 19061483
79 Musich P R, Zou Y (2009). Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A. Aging (Albany, NY), 1(1): 28–37
https://doi.org/10.18632/aging.100012 pmid: 19851476
80 Musich P R, Zou Y (2011). DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome. Biochem Soc Trans, 39(6): 1764–1769
https://doi.org/10.1042/BST20110687 pmid: 22103522
81 Norbury C J, Zhivotovsky B (2004). DNA damage-induced apoptosis. Oncogene, 23(16): 2797–2808
https://doi.org/10.1038/sj.onc.1207532 pmid: 15077143
82 Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park S K, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright S M, Mills K D, Bonni A, Yankner B A, Scully R, Prolla T A, Alt F W, Sinclair D A (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell, 135(5): 907–918
https://doi.org/10.1016/j.cell.2008.10.025 pmid: 19041753
83 Olcina M M, Foskolou I P, Anbalagan S, Senra J M, Pires I M, Jiang Y, Ryan A J, Hammond E M (2013). Replication stress and chromatin context link ATM activation to a role in DNA replication. Mol Cell, 52(5): 758–766
https://doi.org/10.1016/j.molcel.2013.10.019 pmid: 24268576
84 Oshima J, Martin G M, Hisama F M (1993). Werner Syndrome. GeneReviews(R), eds. Pagon R A, Adam M P, Ardinger H H, Wallace S E, Amemiya A, Bean L J H, Bird T D, Fong C T, Mefford H C, Smith R J H, . (University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. Seattle (WA)).
85 Osorio F G, Navarro C L, Cadiñanos J, López-Mejía I C, Quirós P M, Bartoli C, Rivera J, Tazi J, Guzmán G, Varela I, Depetris D, de Carlos F, Cobo J, Andrés V, De Sandre-Giovannoli A, Freije J M, Lévy N, López-Otín C (2011). Splicing-directed therapy in a new mouse model of human accelerated aging. Sci Transl Med, 3(106): 106ra107
https://doi.org/10.1126/scitranslmed.3002847 pmid: 22030750
86 Pagano G, Talamanca A A, Castello G, Cordero M D, d’Ischia M, Gadaleta M N, Pallardó F V, Petrović S, Tiano L, Zatterale A (2014). Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev, 2014: 541230
https://doi.org/10.1155/2014/541230 pmid: 24876913
87 Panier S, Boulton S J (2014). Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol, 15(1): 7–18
https://doi.org/10.1038/nrm3719 pmid: 24326623
88 Patel A G, Sarkaria J N, Kaufmann S H (2011). Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci USA, 108(8): 3406–3411
https://doi.org/10.1073/pnas.1013715108 pmid: 21300883
89 Paull T T, Rogakou E P, Yamazaki V, Kirchgessner C U, Gellert M, Bonner W M (2000). A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol, 10(15): 886–895
https://doi.org/10.1016/S0960-9822(00)00610-2 pmid: 10959836
90 Pegoraro G, Kubben N, Wickert U, Göhler H, Hoffmann K, Misteli T (2009). Ageing-related chromatin defects through loss of the NURD complex. Nat Cell Biol, 11(10): 1261–1267
https://doi.org/10.1038/ncb1971 pmid: 19734887
91 Peinado J R, Quirós P M, Pulido M R, Mariño G, Martínez-Chantar M L, Vázquez-Martínez R, Freije J M P, López-Otín C, Malagón M M (2011). Proteomic profiling of adipose tissue from Zmpste24−/− mice, a model of lipodystrophy and premature aging, reveals major changes in mitochondrial function and vimentin processing. Mol Cell Proteomics, 10(11): M111.008094
92 Polo S E, Jackson S P (2011). Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev, 25(5): 409–433
https://doi.org/10.1101/gad.2021311 pmid: 21363960
93 Price B D, D’Andrea A D (2013). Chromatin remodeling at DNA double-strand breaks. Cell, 152(6): 1344–1354
https://doi.org/10.1016/j.cell.2013.02.011 pmid: 23498941
94 Ray Chaudhuri A, Hashimoto Y, Herrador R, Neelsen K J, Fachinetti D, Bermejo R, Cocito A, Costanzo V, Lopes M (2012). Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol, 19(4): 417–423
https://doi.org/10.1038/nsmb.2258 pmid: 22388737
95 Redwood A B, Gonzalez-Suarez I, Gonzalo S (2011). Regulating the levels of key factors in cell cycle and DNA repair: new pathways revealed by lamins. Cell Cycle, 10(21): 3652–3657
https://doi.org/10.4161/cc.10.21.18201 pmid: 22045204
96 Redwood A B, Perkins S M, Vanderwaal R P, Feng Z, Biehl K J, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti J L, Stewart C L, Zhang J, Gonzalo S (2011). A dual role for A-type lamins in DNA double-strand break repair. Cell Cycle, 10(15): 2549–2560
https://doi.org/10.4161/cc.10.15.16531 pmid: 21701264
97 Richards S A, Muter J, Ritchie P, Lattanzi G, Hutchison C J (2011). The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine. Hum Mol Genet, 20(20): 3997–4004
https://doi.org/10.1093/hmg/ddr327 pmid: 21807766
98 Rivera-Torres J, Acín-Perez R, Cabezas-Sánchez P, Osorio F G, Gonzalez-Gómez C, Megias D, Cámara C, López-Otín C, Enríquez J A, Luque-García J L, Andrés V (2013). Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. J Proteomics, 91: 466–477
https://doi.org/10.1016/j.jprot.2013.08.008 pmid: 23969228
99 Roos W P, Kaina B (2006). DNA damage-induced cell death by apoptosis. Trends Mol Med, 12(9): 440–450
https://doi.org/10.1016/j.molmed.2006.07.007 pmid: 16899408
100 Sahin E, Depinho R A (2010). Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature, 464(7288): 520–528
https://doi.org/10.1038/nature08982 pmid: 20336134
101 Scaffidi P, Misteli T (2005). Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med, 11(4): 440–445
https://doi.org/10.1038/nm1204 pmid: 15750600
102 Schmitt E, Paquet C, Beauchemin M, Bertrand R (2007). DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis. J Zhejiang Univ Sci B, 8(6): 377–397
https://doi.org/10.1631/jzus.2007.B0377 pmid: 17565509
103 Schreiber K H, Kennedy B K (2013). When lamins go bad: nuclear structure and disease. Cell, 152(6): 1365–1375
https://doi.org/10.1016/j.cell.2013.02.015 pmid: 23498943
104 Shiloh Y, Ziv Y (2013). The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol, 14(4): 197–210
https://doi.org/10.1038/nrm3546
105 Shrivastav M, De Haro L P, Nickoloff J A (2008). Regulation of DNA double-strand break repair pathway choice. Cell Res, 18(1): 134–147
https://doi.org/10.1038/cr.2007.111 pmid: 18157161
106 Shumaker D K, Dechat T, Kohlmaier A, Adam S A, Bozovsky M R, Erdos M R, Eriksson M, Goldman A E, Khuon S, Collins F S, Jenuwein T, Goldman R D (2006). Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci USA, 103(23): 8703–8708
https://doi.org/10.1073/pnas.0602569103 pmid: 16738054
107 Singh M, Hunt C R, Pandita R K, Kumar R, Yang C R, Horikoshi N, Bachoo R, Serag S, Story M D, Shay J W, Powell S N, Gupta A, Jeffery J, Pandita S, Chen B P, Deckbar D, Löbrich M, Yang Q, Khanna K K, Worman H J, Pandita T K (2013). Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest. Mol Cell Biol, 33(6): 1210–1222
https://doi.org/10.1128/MCB.01676-12 pmid: 23319047
108 Sirbu B M, Cortez D (2013). DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol, 5(8): a012724
https://doi.org/10.1101/cshperspect.a012724 pmid: 23813586
109 Stewart G S, Wang B, Bignell C R, Taylor A M, Elledge S J (2003). MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature, 421(6926): 961–966
https://doi.org/10.1038/nature01446 pmid: 12607005
110 Stiff T, O’Driscoll M, Rief N, Iwabuchi K, Löbrich M, Jeggo P A (2004). ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res, 64(7): 2390–2396
https://doi.org/10.1158/0008-5472.CAN-03-3207 pmid: 15059890
111 Sun Y, Jiang X, Chen S, Fernandes N, Price B D (2005). A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA, 102(37): 13182–13187
https://doi.org/10.1073/pnas.0504211102 pmid: 16141325
112 Sun Y, Jiang X, Xu Y, Ayrapetov M K, Moreau L A, Whetstine J R, Price B D (2009). Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol, 11(11): 1376–1382
https://doi.org/10.1038/ncb1982 pmid: 19783983
113 Tang H, Hilton B, Musich P R, Fang D Z, Zou Y (2012). Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson-Gilford progeria syndrome. Aging Cell, 11(2): 363–365
https://doi.org/10.1111/j.1474-9726.2011.00779.x pmid: 22168243
114 Tubbs A T, Sleckman B P (2014). ATM deficiency: revealing the pathways to cancer. Cell Cycle, 13(19): 2992
https://doi.org/10.4161/15384101.2014.959849 pmid: 25486558
115 Varga R, Eriksson M, Erdos M R, Olive M, Harten I, Kolodgie F, Capell B C, Cheng J, Faddah D, Perkins S, Avallone H, San H, Qu X, Ganesh S, Gordon L B, Virmani R, Wight T N, Nabel E G, Collins F S (2006). Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA, 103(9): 3250–3255
https://doi.org/10.1073/pnas.0600012103 pmid: 16492728
116 Verstraeten V L, Peckham L A, Olive M, Capell B C, Collins F S, Nabel E G, Young S G, Fong L G, Lammerding J (2011). Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect. Proc Natl Acad Sci USA, 108(12): 4997–5002
https://doi.org/10.1073/pnas.1019532108 pmid: 21383178
117 Viteri G, Chung Y W, Stadtman E R (2010). Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients. Mech Ageing Dev, 131(1): 2–8
https://doi.org/10.1016/j.mad.2009.11.006 pmid: 19958786
118 Ward I M, Chen J (2001). Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem, 276(51): 47759–47762
pmid: 11673449
119 Xiong Z M, Choi J Y, Wang K, Zhang H, Tariq Z, Wu D, Ko E, LaDana C, Sesaki H, Cao K (2015). Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell
pmid: 26663466
120 Xiong Z M, Choi J Y, Wang K, Zhang H, Tariq Z, Wu D, Ko E, LaDana C, Sesaki H, Cao K (2016). Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria. Aging Cell, 15(2): 279–290
https://doi.org/10.1111/acel.12434 pmid: 26663466
121 Yang S H, Meta M, Qiao X, Frost D, Bauch J, Coffinier C, Majumdar S, Bergo M O, Young S G, Fong L G (2006). A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J Clin Invest, 116(8): 2115–2121
https://doi.org/10.1172/JCI28968 pmid: 16862216
122 Yang S H, Qiao X, Fong L G, Young S G (2008). Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation. Biochim Biophys Acta, 1781(1-2): 36–39
https://doi.org/10.1016/j.bbalip.2007.11.003 pmid: 18082640
123 Zhang H, Kieckhaefer J E, Cao K (2013). Mouse models of laminopathies. Aging Cell, 12(1): 2–10
https://doi.org/10.1111/acel.12021 pmid: 23095062
124 Zhang H, Xiong Z M, Cao K (2014). Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci USA, 111(22): E2261–E2270
https://doi.org/10.1073/pnas.1320843111 pmid: 24843141
125 Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T, Yang J, Li Y, Shi L, Guan D, Pan H, Duan S, Ding Z, Li M, Yi F, Bai R, Wang Y, Chen C, Yang F, Li X, Wang Z, Aizawa E, Goebl A, Soligalla R D, Reddy P, Esteban C R, Tang F, Liu G H, Belmonte J C (2015). Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science, 348(6239): 1160–1163
https://doi.org/10.1126/science.aaa1356 pmid: 25931448
126 Zhou B B, Elledge S J (2000). The DNA damage response: putting checkpoints in perspective. Nature, 408(6811): 433–439
https://doi.org/10.1038/35044005 pmid: 11100718
127 Zimmermann M, Lottersberger F, Buonomo S B, Sfeir A, de Lange T (2013). 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science, 339(6120): 700–704
https://doi.org/10.1126/science.1231573 pmid: 23306437
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