多能干细胞维持遗传物质稳定性的调控机制
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摘要
多能干细胞(pluripotent stem cells,PSCs)能无限增殖且具有发育多潜能性,在再生医学中有巨大的应用前景,但长期扩增过程中产生的遗传物质不稳定性及潜在致瘤性阻碍了临床应用。深入理解多能干细胞维持遗传物质稳定性的方式和机制具有重要的理论价值和应用前景。由于功能的特殊性,相较于体细胞,多能干细胞维持遗传物质稳定性的能力更强,并有其独特的机制。该文简要综述了近年来在多能干细胞维持遗传物质稳定性方面的研究进展,包括干细胞如何有效应对DNA复制压力、如何有效修复DNA损伤以及在DNA损伤情况下的细胞命运决定机制。
Pluripotent stem cells(PSCs) hold great promise for cell-based regenerative medicine. However, genomic instability and tumorigenicity hamper their full applications. Understanding the mechanisms that regulate their genome stability is critical to address this issue. Due to the specific functional purpose, PSCs possess high competence to safeguard genomic stability by employing specific strategies. In this review, we summarized the current progress in understanding the mechanisms that the PSCs utilize to cope with DNA replication stress, to repair DNA damage, and to determine the cell fates after unrepairable damage.
Pluripotent stem cells(PSCs) hold great promise for cell-based regenerative medicine. However, genomic instability and tumorigenicity hamper their full applications. Understanding the mechanisms that regulate their genome stability is critical to address this issue. Due to the specific functional purpose, PSCs possess high competence to safeguard genomic stability by employing specific strategies. In this review, we summarized the current progress in understanding the mechanisms that the PSCs utilize to cope with DNA replication stress, to repair DNA damage, and to determine the cell fates after unrepairable damage.
引文
1 Tichy ED,Stambrook PJ.DNA repair in murine embryonic stem cells and differentiated cells.Exp Cell Res 2008;314(9):1929-36.
2 Zhao B,Zhang WD,Duan YL,Lu YQ,Cun YX,Li CH,et al.Filia is an ESC-specific regulator of DNA damage response and safeguards genomic stability.Cell Stem Cell 2015;16(6):684-98.
3 Maynard S,Swistowska AM,Lee JW,Liu Y,Liu ST,Da Cruz AB,et al.Human embryonic stem cells have enhanced repair of multiple forms of DNA damage.Stem Cells 2008;26(9):2266-74.
4 Cho YM,Kwon S,Pak YK,Seol HW,Choi YM,Park DJ,et al.Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells.Biochem Biophys Res Commun 2006;348(4):1472-8.
5 Xu X,Duan S,Yi F,Ocampo A,Liu GH,Izpisua Belmonte JC.Mitochondrial regulation in pluripotent stem cells.Cell Metab2013;18(3):325-32.
6 Ge XQ,Han J,Cheng EC,Yamaguchi S,Shima N,Thomas JL,et al.Embryonic stem cells license a high level of dormant origins to protect the genome against replication stress.Stem Cell Reports 2015;5(2):185-94.
7 Zhao B,Zhang W,Cun Y,Li J,Liu Y,Gao J,et al.Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex.Cell Res 2018;28(1):69-89.
8 Zalzman M,Falco G,Sharova LV,Nishiyama A,Thomas M,Lee SL,et al.Zscan4 regulates telomere elongation and genomic stability in ES cells.Nature 2010;464(7290):858-63.
9 Vitale I,Manic G,De Maria R,Kroemer G,Galluzzi L.DNA damage in stem cells.Mol Cell 2017;66(3):306-19.
10 Oliveira PH,da Silva CL,Cabral JM.Concise review:genomic instability in human stem cells:current status and future challenges.Stem Cells 2014;32(11):2824-32.
11 Hong Y,Cervantes RB,Tichy E,Tischfield JA,Stambrook PJ.Protecting genomic integrity in somatic cells and embryonic stem cells.Mutat Res 2007;614(1/2):48-55.
12 Gonfloni S.Targeting DNA damage response:threshold,chromatin landscape and beyond.Pharmacol Ther 2013;138(1):46-52.
13 Cimprich KA,Cortez D.ATR:an essential regulator of genome integrity.Nat Rev Mol Cell Biol 2008;9(8):616-27.
14 Farber-Katz SE,Dippold HC,Buschman MD,Peterman MC,Xing M,Noakes CJ,et al.DNA damage triggers golgi dispersal via DNA-PK and GOLPH3.Cell 2014;156(3):413-27.
15 Cevher MA,Kleiman FE.Connections between 3′-end processing and DNA damage response.Wiley Interdiscip Rev RNA2010;1(1):193-9.
16 Rooney JP,George AD,Patil A,Begley U,Bessette E,Zappala MR,et al.Systems based mapping demonstrates that recovery from alkylation damage requires DNA repair,RNA processing,and translation associated networks.Genomics 2009;93(1):42-51.
17 Reinhardt HC,Cannell IG,Morandell S,Yaffe MB.Is posttranscriptional stabilization,splicing and translation of selective m RNAs a key to the DNA damage response?Cell Cycle 2011;10(1):23-7.
18 Lagerwerf S,Vrouwe MG,Overmeer RM,Fousteri MI,Mullenders LH.DNA damage response and transcription.DNA Repair(Amst)2011;10(7):743-50.
19 de Laat WL,Jaspers NG,Hoeijmakers JH.Molecular mechanism of nucleotide excision repair.Genes Dev 1999;13(7):768-85.
20 Boucas J,Riabinska A,Jokic M,Herter-Sprie GS,Chen S,H?pker K,et al.Posttranscriptional regulation of gene expressionadding another layer of complexity to the DNA damage response.Front Genet 2012;3:159.
21 Panier S,Ichijima Y,Fradet-Turcotte A,Leung CC,Kaustov L,Arrowsmith CH,et al.Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks.Mol Cell 2012;47(3):383-95.
22 Liang Y,Lin SY,Brunicardi FC,Goss J,Li K.DNA damage response pathways in tumor suppression and cancer treatment.World J Surg 2009;33(4):661-6.
23 Blanpain C,Mohrin M,Sotiropoulou PA,PasseguéE.DNAdamage response in tissue-specific and cancer stem cells.Cell Stem Cell 2011;8(1):16-29.
24 Stambrook PJ,Tichy ED.Preservation of genomic integrity in mouse embryonic stem cells.Adv Exp Med Biol 2010;695:59-75.
25 Blagosklonny MV,Pardee AB.The restriction point of the cell cycle.Cell Cycle 2002;1(2):103-10.
26 Filion TM,Qiao M,Ghule PN,Mandeville M,van Wijnen AJ,Stein JL,et al.Survival responses of human embryonic stem cells to DNA damage.J Cell Physiol 2009;220(3):586-92.
27 Chuykin IA,Lianguzova MS,Pospelova TV,Pospelov VA.Activation of DNA damage response signaling in mouse embryonic stem cells.Cell Cycle 2008;7(18):2922-8.
28 Tichy ED,Pillai R,Deng L,Liang L,Tischfield J,Schwemberger SJ,et al.Mouse embryonic stem cells,but not somatic cells,predominantly use homologous recombination to repair doublestrand DNA breaks.Stem Cells Dev 2010;19(11):1699-711.
29 Serrano L,Liang L,Chang Y,Deng L,Maulion C,Nguyen S,et al.Homologous recombination conserves DNA sequence integrity throughout the cell cycle in embryonic stem cells.Stem Cells Dev 2011;20(2):363-74.
30 Liu JC,Guan X,Ryan JA,Rivera AG,Mock C,Agrawal V,et al.High mitochondrial priming sensitizes h ESCs to DNA-damageinduced apoptosis.Cell Stem Cell 2013;13(4):483-91.
31 Dumitru R,Gama V,Fagan BM,Bower JJ,Swahari V,Pevny LH,et al.Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis.Mol Cell 2012;46(5):573-83.
32 Lin T,Chao C,Saito S,Mazur SJ,Murphy ME,Appella E,et al.p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression.Nat Cell Biol 2005;7(2):165-71.
33 Pines A,Kelstrup CD,Vrouwe MG,Puigvert JC,Typas D,Misovic B,et al.Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells.Mol Cell Biol 2011;31(24):4964-77.
34 Carreras Puigvert J,von Stechow L,Siddappa R,Pines A,Bahjat M,Haazen LC,et al.Systems biology approach identifies the kinase csnk1a1 as a regulator of the DNA damage response in embryonic stem cells.Sci Signal 2013;6(259):ra5.
35 Zheng P,Dean J.Role of Filia,a maternal effect gene,in maintaining euploidy during cleavage-stage mouse embryo-genesis.Proc Natl Acad Sci USA 2009;106(18):7473-8.
36 Chambers I,Colby D,Robertson M,Nichols J,Lee S,Tweedie S,et al.Functional expression cloning of Nanog,a pluripotency sustaining factor in embryonic stem cells.Cell 2003;113(5):643-55.
37 Traven A,Heierhorst J.SQ/TQ cluster domains:concentrated ATM/ATR kinase phosphorylation site regions in DNA-damageresponse proteins.Bioessays 2005;27(4):397-407.
38 Wu L.Role of the BLM helicase in replication fork management.DNA Repair(Amst)2007;6(7):936-44.
39 Zhang SS,Hernmerich P,Grosse F.Centrosomal localization of DNA damage checkpoint proteins.J Cell Biochem 2007;101(2):451-65.
40 Xiong J,Todorova D,Su NY,Kim J,Lee PJ,Shen Z,et al.Stemness factor Sall4 is required for DNA damage response in embryonic stem cells.J Cell Biol 2015;208(5):513-20.
41 Zeman MK,Cimprich KA.Causes and consequences of replication stress.Nat Cell Biol 2014;16(1):2-9.
42 Harper JW,Elledge SJ.The DNA damage response:Ten years after.Mol Cell 2007;28(5):739-45.
43 Bass TE,Luzwick JW,Kavanaugh G,Carroll C,Dungrawala H,Glick GG,et al.ETAA1 acts at stalled replication forks to maintain genome integrity.Nat Cell Biol 2016;18(11):1185.
44 Lee YC,Zhou Q,Chen J,Yuan J.RPA-binding protein ETAA1is an ATR activator involved in DNA replication stress response.Curr Biol 2016;26(24):3257-68.
45 Techer H,Koundrioukoff S,Azar D,Wilhelm T,Carignon S,Brison O,et al.Replication dynamics:biases and robustness of DNA fiber analysis.J Mol Biol 2013;425(23):4845-55.
46 Sirbu BM,Couch FB,Cortez D.Monitoring the spatiotemporal dynamics of proteins at replication forks and in assembled chromatin using isolation of proteins on nascent DNA.Nat Protoc2012;7(3):594-605.
47 Schwab RA,Niedzwiedz W.Visualization of DNA replication in the vertebrate model system DT40 using the DNA fiber technique.J Vis Exp 2011(56):e3255.
48 Savatier P,Lapillonne H,Jirmanova L,Vitelli L,Samarut J.Analysis of the cell cycle in mouse embryonic stem cells.Methods Mol Biol 2002;185:27-33.
49 Banath JP,Ba?uelos CA,Klokov D,Mac Phail SM,Lansdorp PM,Olive PL.Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells.Exp Cell Res 2009;315(8):1505-20.
50 Ahuja AK,Jodkowska K,Teloni F,Bizard AH,Zellweger R,Herrador R,et al.A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells.Nat Commun 2016;7:10660.
51 Petermann E,Orta ML,Issaeva N,Schultz N,Helleday T.Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair.Mol Cell 2010;37(4):492-502.
52 Davies SL,North PS,Hickson ID.Role for BLM in replicationfork restart and suppression of origin firing after replicative stress.Nat Struct Mol Biol 2007;14(7):677-9.
2 Zhao B,Zhang WD,Duan YL,Lu YQ,Cun YX,Li CH,et al.Filia is an ESC-specific regulator of DNA damage response and safeguards genomic stability.Cell Stem Cell 2015;16(6):684-98.
3 Maynard S,Swistowska AM,Lee JW,Liu Y,Liu ST,Da Cruz AB,et al.Human embryonic stem cells have enhanced repair of multiple forms of DNA damage.Stem Cells 2008;26(9):2266-74.
4 Cho YM,Kwon S,Pak YK,Seol HW,Choi YM,Park DJ,et al.Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells.Biochem Biophys Res Commun 2006;348(4):1472-8.
5 Xu X,Duan S,Yi F,Ocampo A,Liu GH,Izpisua Belmonte JC.Mitochondrial regulation in pluripotent stem cells.Cell Metab2013;18(3):325-32.
6 Ge XQ,Han J,Cheng EC,Yamaguchi S,Shima N,Thomas JL,et al.Embryonic stem cells license a high level of dormant origins to protect the genome against replication stress.Stem Cell Reports 2015;5(2):185-94.
7 Zhao B,Zhang W,Cun Y,Li J,Liu Y,Gao J,et al.Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex.Cell Res 2018;28(1):69-89.
8 Zalzman M,Falco G,Sharova LV,Nishiyama A,Thomas M,Lee SL,et al.Zscan4 regulates telomere elongation and genomic stability in ES cells.Nature 2010;464(7290):858-63.
9 Vitale I,Manic G,De Maria R,Kroemer G,Galluzzi L.DNA damage in stem cells.Mol Cell 2017;66(3):306-19.
10 Oliveira PH,da Silva CL,Cabral JM.Concise review:genomic instability in human stem cells:current status and future challenges.Stem Cells 2014;32(11):2824-32.
11 Hong Y,Cervantes RB,Tichy E,Tischfield JA,Stambrook PJ.Protecting genomic integrity in somatic cells and embryonic stem cells.Mutat Res 2007;614(1/2):48-55.
12 Gonfloni S.Targeting DNA damage response:threshold,chromatin landscape and beyond.Pharmacol Ther 2013;138(1):46-52.
13 Cimprich KA,Cortez D.ATR:an essential regulator of genome integrity.Nat Rev Mol Cell Biol 2008;9(8):616-27.
14 Farber-Katz SE,Dippold HC,Buschman MD,Peterman MC,Xing M,Noakes CJ,et al.DNA damage triggers golgi dispersal via DNA-PK and GOLPH3.Cell 2014;156(3):413-27.
15 Cevher MA,Kleiman FE.Connections between 3′-end processing and DNA damage response.Wiley Interdiscip Rev RNA2010;1(1):193-9.
16 Rooney JP,George AD,Patil A,Begley U,Bessette E,Zappala MR,et al.Systems based mapping demonstrates that recovery from alkylation damage requires DNA repair,RNA processing,and translation associated networks.Genomics 2009;93(1):42-51.
17 Reinhardt HC,Cannell IG,Morandell S,Yaffe MB.Is posttranscriptional stabilization,splicing and translation of selective m RNAs a key to the DNA damage response?Cell Cycle 2011;10(1):23-7.
18 Lagerwerf S,Vrouwe MG,Overmeer RM,Fousteri MI,Mullenders LH.DNA damage response and transcription.DNA Repair(Amst)2011;10(7):743-50.
19 de Laat WL,Jaspers NG,Hoeijmakers JH.Molecular mechanism of nucleotide excision repair.Genes Dev 1999;13(7):768-85.
20 Boucas J,Riabinska A,Jokic M,Herter-Sprie GS,Chen S,H?pker K,et al.Posttranscriptional regulation of gene expressionadding another layer of complexity to the DNA damage response.Front Genet 2012;3:159.
21 Panier S,Ichijima Y,Fradet-Turcotte A,Leung CC,Kaustov L,Arrowsmith CH,et al.Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks.Mol Cell 2012;47(3):383-95.
22 Liang Y,Lin SY,Brunicardi FC,Goss J,Li K.DNA damage response pathways in tumor suppression and cancer treatment.World J Surg 2009;33(4):661-6.
23 Blanpain C,Mohrin M,Sotiropoulou PA,PasseguéE.DNAdamage response in tissue-specific and cancer stem cells.Cell Stem Cell 2011;8(1):16-29.
24 Stambrook PJ,Tichy ED.Preservation of genomic integrity in mouse embryonic stem cells.Adv Exp Med Biol 2010;695:59-75.
25 Blagosklonny MV,Pardee AB.The restriction point of the cell cycle.Cell Cycle 2002;1(2):103-10.
26 Filion TM,Qiao M,Ghule PN,Mandeville M,van Wijnen AJ,Stein JL,et al.Survival responses of human embryonic stem cells to DNA damage.J Cell Physiol 2009;220(3):586-92.
27 Chuykin IA,Lianguzova MS,Pospelova TV,Pospelov VA.Activation of DNA damage response signaling in mouse embryonic stem cells.Cell Cycle 2008;7(18):2922-8.
28 Tichy ED,Pillai R,Deng L,Liang L,Tischfield J,Schwemberger SJ,et al.Mouse embryonic stem cells,but not somatic cells,predominantly use homologous recombination to repair doublestrand DNA breaks.Stem Cells Dev 2010;19(11):1699-711.
29 Serrano L,Liang L,Chang Y,Deng L,Maulion C,Nguyen S,et al.Homologous recombination conserves DNA sequence integrity throughout the cell cycle in embryonic stem cells.Stem Cells Dev 2011;20(2):363-74.
30 Liu JC,Guan X,Ryan JA,Rivera AG,Mock C,Agrawal V,et al.High mitochondrial priming sensitizes h ESCs to DNA-damageinduced apoptosis.Cell Stem Cell 2013;13(4):483-91.
31 Dumitru R,Gama V,Fagan BM,Bower JJ,Swahari V,Pevny LH,et al.Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis.Mol Cell 2012;46(5):573-83.
32 Lin T,Chao C,Saito S,Mazur SJ,Murphy ME,Appella E,et al.p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression.Nat Cell Biol 2005;7(2):165-71.
33 Pines A,Kelstrup CD,Vrouwe MG,Puigvert JC,Typas D,Misovic B,et al.Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells.Mol Cell Biol 2011;31(24):4964-77.
34 Carreras Puigvert J,von Stechow L,Siddappa R,Pines A,Bahjat M,Haazen LC,et al.Systems biology approach identifies the kinase csnk1a1 as a regulator of the DNA damage response in embryonic stem cells.Sci Signal 2013;6(259):ra5.
35 Zheng P,Dean J.Role of Filia,a maternal effect gene,in maintaining euploidy during cleavage-stage mouse embryo-genesis.Proc Natl Acad Sci USA 2009;106(18):7473-8.
36 Chambers I,Colby D,Robertson M,Nichols J,Lee S,Tweedie S,et al.Functional expression cloning of Nanog,a pluripotency sustaining factor in embryonic stem cells.Cell 2003;113(5):643-55.
37 Traven A,Heierhorst J.SQ/TQ cluster domains:concentrated ATM/ATR kinase phosphorylation site regions in DNA-damageresponse proteins.Bioessays 2005;27(4):397-407.
38 Wu L.Role of the BLM helicase in replication fork management.DNA Repair(Amst)2007;6(7):936-44.
39 Zhang SS,Hernmerich P,Grosse F.Centrosomal localization of DNA damage checkpoint proteins.J Cell Biochem 2007;101(2):451-65.
40 Xiong J,Todorova D,Su NY,Kim J,Lee PJ,Shen Z,et al.Stemness factor Sall4 is required for DNA damage response in embryonic stem cells.J Cell Biol 2015;208(5):513-20.
41 Zeman MK,Cimprich KA.Causes and consequences of replication stress.Nat Cell Biol 2014;16(1):2-9.
42 Harper JW,Elledge SJ.The DNA damage response:Ten years after.Mol Cell 2007;28(5):739-45.
43 Bass TE,Luzwick JW,Kavanaugh G,Carroll C,Dungrawala H,Glick GG,et al.ETAA1 acts at stalled replication forks to maintain genome integrity.Nat Cell Biol 2016;18(11):1185.
44 Lee YC,Zhou Q,Chen J,Yuan J.RPA-binding protein ETAA1is an ATR activator involved in DNA replication stress response.Curr Biol 2016;26(24):3257-68.
45 Techer H,Koundrioukoff S,Azar D,Wilhelm T,Carignon S,Brison O,et al.Replication dynamics:biases and robustness of DNA fiber analysis.J Mol Biol 2013;425(23):4845-55.
46 Sirbu BM,Couch FB,Cortez D.Monitoring the spatiotemporal dynamics of proteins at replication forks and in assembled chromatin using isolation of proteins on nascent DNA.Nat Protoc2012;7(3):594-605.
47 Schwab RA,Niedzwiedz W.Visualization of DNA replication in the vertebrate model system DT40 using the DNA fiber technique.J Vis Exp 2011(56):e3255.
48 Savatier P,Lapillonne H,Jirmanova L,Vitelli L,Samarut J.Analysis of the cell cycle in mouse embryonic stem cells.Methods Mol Biol 2002;185:27-33.
49 Banath JP,Ba?uelos CA,Klokov D,Mac Phail SM,Lansdorp PM,Olive PL.Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells.Exp Cell Res 2009;315(8):1505-20.
50 Ahuja AK,Jodkowska K,Teloni F,Bizard AH,Zellweger R,Herrador R,et al.A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells.Nat Commun 2016;7:10660.
51 Petermann E,Orta ML,Issaeva N,Schultz N,Helleday T.Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair.Mol Cell 2010;37(4):492-502.
52 Davies SL,North PS,Hickson ID.Role for BLM in replicationfork restart and suppression of origin firing after replicative stress.Nat Struct Mol Biol 2007;14(7):677-9.