Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma
Autoři:
Pilar Delgado aff001; Ángel F. Álvarez-Prado aff001; Ester Marina-Zárate aff001; Isora V. Sernandez aff001; Sonia M. Mur aff001; Jorge de la Barrera aff002; Fátima Sanchez-Cabo aff002; Marta Cañamero aff003; Antonio de Molina aff004; Laura Belver aff001; Virginia G. de Yébenes aff001; Almudena R. Ramiro aff001
Působiště autorů:
B Lymphocyte Biology Lab. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff001; Bioinformatics Unit. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff002; Roche Pharma, Penzberg, Germany
aff003; Comparative Medicine Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
aff004
Vyšlo v časopise:
Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma. PLoS Genet 16(12): e1008960. doi:10.1371/journal.pgen.1008960
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008960
Souhrn
Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supra-activity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.
Klíčová slova:
Carcinogenesis – B cells – Cancers and neoplasms – Malignant tumors – Mammalian genomics – Mouse models – Spleen
Zdroje
1. Shaffer AL 3rd, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565–610. Epub 2012/01/10. doi: 10.1146/annurev-immunol-020711-075027 22224767.
2. Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 2015;15(3):172–84. Epub 2015/02/26. doi: 10.1038/nri3814 25712152.
3. Mlynarczyk C, Fontán L, Melnick A. Germinal center-derived lymphomas: The darkest side of humoral immunity. Immunological Reviews. 2019;288(1):214–39. doi: 10.1111/imr.12755 30874354
4. Methot SP, Di Noia JM. Molecular Mechanisms of Somatic Hypermutation and Class Switch Recombination. Advances in Immunology. 2017;133:37–87. doi: 10.1016/bs.ai.2016.11.002 28215280
5. Victora GD, Nussenzweig MC. Germinal Centers. Annual Review of Immunology. 2012;30(1):429–57. doi: 10.1146/annurev-immunol-020711-075032 22224772.
6. Stavnezer J, Guikema JEJ, Schrader CE. Mechanism and Regulation of Class Switch Recombination. Annual Review of Immunology. 2008;26:261–92. doi: 10.1146/annurev.immunol.26.021607.090248 18370922
7. Di Noia JM, Neuberger MS. Molecular Mechanisms of Antibody Somatic Hypermutation. Annual Review of Biochemistry. 2007;76:1–22. doi: 10.1146/annurev.biochem.76.061705.090740 17328676
8. Roco JA, Mesin L, Binder SC, Nefzger C, Gonzalez-Figueroa P, Canete PF, et al. Class-Switch Recombination Occurs Infrequently in Germinal Centers. Immunity. 2019;51(2):337–50.e7. doi: 10.1016/j.immuni.2019.07.001 31375460
9. Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2). Cell. 2000;102:565–75. doi: 10.1016/s0092-8674(00)00079-9 11007475
10. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme. Cell. 2000;102:553–63. doi: 10.1016/s0092-8674(00)00078-7 11007474
11. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. Immunoglobulin Isotype Switching Is Inhibited and Somatic Hypermutation Perturbed in UNG-Deficient Mice. Current Biology. 2002;12:1748–55. doi: 10.1016/s0960-9822(02)01215-0 12401169
12. Rada C, Ehrenstein MR, Neuberger MS, Milstein C. Hot Spot Focusing of Somatic Hypermutation in MSH2-Deficient Mice Suggests Two Stages of Mutational Targeting. Immunity. 1998;9:135–41. doi: 10.1016/s1074-7613(00)80595-6 9697843
13. Ehrenstein MR, Neuberger MS. Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation. The EMBO Journal. 1999;18(12):3484–90. doi: 10.1093/emboj/18.12.3484 10369687
14. Petersen-Mahrt SK, Harris RS, Neuberger MS. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature. 2002;418:99–104. doi: 10.1038/nature00862 12097915
15. Noia JD, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature. 2002;419(6902):43. doi: 10.1038/nature00981 12214226
16. Phung QH, Winter DB, Cranston A, Tarone RE, Bohr VA, Fishel R, et al. Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein. The Journal of Experimental Medicine. 1998;187:1745–51. doi: 10.1084/jem.187.11.1745 9607916
17. Maul RW, Saribasak H, Martomo SA, McClure RL, Yang W, Vaisman A, et al. Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions. Nat Immunol. 2011;12(1):70–6. Epub 2010/12/15. doi: 10.1038/ni.1970 21151102; PubMed Central PMCID: PMC3653439.
18. Wiesendanger M, Kneitz B, Edelmann W, Scharff MD. Somatic hypermutation in MutS homologue (MSH)3-, MSH6-, and MSH3/MSH6-deficient mice reveals a role for the MSH2-MSH6 heterodimer in modulating the base substitution pattern. J Exp Med. 2000;191(3):579–84. Epub 2000/02/09. doi: 10.1084/jem.191.3.579 10662804; PubMed Central PMCID: PMC2195810.
19. Rada C, Di Noia JM, Neuberger MS. Mismatch Recognition and Uracil Excision Provide Complementary Paths to Both Ig Switching and the A/T-Focused Phase of Somatic Mutation. Molecular Cell. 2004;16:163–71. doi: 10.1016/j.molcel.2004.10.011 15494304
20. Álvarez-Prado ÁF, Pérez-Durán P, Pérez-García A, Benguria A, Torroja C, Yébenes VGd, et al. A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets. Journal of Experimental Medicine. 2018;215(3):761–71. doi: 10.1084/jem.20171738 29374026
21. Shen HM, Peters A, Baron B, Zhu X, Storb U. Mutation of BCL-6 Gene in Normal B Cells by the Process of Somatic Hypermutation of Ig Genes. Science. 1998;280:1750–2. doi: 10.1126/science.280.5370.1750 9624052
22. Pasqualucci L, Migliazza A, Fracchiolla N, William C, Neri A, Baldini L, et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(20):11816–21. doi: 10.1073/pnas.95.20.11816 9751748
23. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RSK, Küppers R, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001;412:341–6. doi: 10.1038/35085588 11460166
24. Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008;451:841–5. doi: 10.1038/nature06547 18273020
25. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen H-T, McBride KM, et al. Role of genomic instability and p53 in AID-induced c-myc–Igh translocations. Nature. 2006;440:105–9. doi: 10.1038/nature04495 16400328
26. Ramiro AR, Jankovic M, Eisenreich T, Difilippantonio S, Chen-Kiang S, Muramatsu M, et al. AID Is Required for c-myc/IgH Chromosome Translocations In Vivo. Cell. 2004;118:431–8. doi: 10.1016/j.cell.2004.08.006 15315756
27. Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, Difilippantonio S, et al. AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations. Cell. 2008;135:1028–38. doi: 10.1016/j.cell.2008.09.062 19070574
28. Klein IA, Resch W, Jankovic M, Oliveira T, Yamane A, Nakahashi H, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011;147:95–106. doi: 10.1016/j.cell.2011.07.048 21962510
29. Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, Ho YJ, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147(1):107–19. doi: 10.1016/j.cell.2011.07.049 21962511; PubMed Central PMCID: PMC3186939.
30. Pérez-Durán P, Belver L, Yébenes VGd, Delgado P, Pisano DG, Ramiro AR. UNG shapes the specificity of AID-induced somatic hypermutation. The Journal of Experimental Medicine. 2012;209:1379–89. doi: 10.1084/jem.20112253 22665573
31. Nilsen H, Stamp G, Andersen S, Hrivnak G, Krokan HE, Lindahl T, et al. Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene. 2003;22(35):5381–6. Epub 2003/08/23. doi: 10.1038/sj.onc.1206860 12934097.
32. Gu X, Booth CJ, Liu Z, Strout MP. AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B-cell lymphoma. Blood. 2016;127(1):102–12. doi: 10.1182/blood-2015-02-628164 26385350
33. Cortizas EM, Zahn A, Safavi S, Reed JA, Vega F, Di Noia JM, et al. UNG protects B cells from AID-induced telomere loss. Journal of Experimental Medicine. 2016;213(11):2459–72. doi: 10.1084/jem.20160635 27697833
34. Safavi S, Larouche A, Zahn A, Patenaude A-M, Domanska D, Dionne K, et al. The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID. NAR Cancer. 2020;2(3). doi: 10.1093/narcan/zcaa019
35. Montamat-Sicotte D, Litzler LC, Abreu C, Safavi S, Zahn A, Orthwein A, et al. HSP90 inhibitors decrease AID levels and activity in mice and in human cells. Eur J Immunol. 2015;45(8):2365–76. doi: 10.1002/eji.201545462 25912253; PubMed Central PMCID: PMC4536124.
36. Robbiani Davide F, Deroubaix S, Feldhahn N, Oliveira Thiago Y, Callen E, Wang Q, et al. Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma. Cell. 2015;162(4):727–37. doi: 10.1016/j.cell.2015.07.019 26276629
37. Pasqualucci L, Bhagat G, Jankovic M, Compagno M, Smith P, Muramatsu M, et al. AID is required for germinal center–derived lymphomagenesis. Nature Genetics. 2008;40(1):108–12. doi: 10.1038/ng.2007.35 18066064
38. Robbiani DF, Nussenzweig MC. Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annu Rev Pathol. 2013;8:79–103. doi: 10.1146/annurev-pathol-020712-164004 22974238.
39. Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon SM, et al. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol. 2015;16(7):766–74. doi: 10.1038/ni.3160 25985233; PubMed Central PMCID: PMC4475638.
40. Müschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Küppers R. Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction. The Journal of Experimental Medicine. 2000;192:1833–40. doi: 10.1084/jem.192.12.1833 11120779
41. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. doi: 10.1038/nature12477 23945592
42. Young RM, Phelan JD, III ALS, Wright GW, Huang DW, Schmitz R, et al. Taming the Heterogeneity of Aggressive Lymphomas for Precision Therapy. Annual Review of Cancer Biology. 2019;3(1):429–55. doi: 10.1146/annurev-cancerbio-030518-055734
43. Kovalchuk AL, duBois W, Mushinski E, McNeil NE, Hirt C, Qi CF, et al. AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements. J Exp Med. 2007;204(12):2989–3001. Epub 2007/11/14. doi: 10.1084/jem.20070882 17998390; PubMed Central PMCID: PMC2118515.
44. Nepal RM, Zaheen A, Basit W, Li L, Berger SA, Martin A. AID and RAG1 do not contribute to lymphomagenesis in Eμ c-myc transgenic mice. Oncogene. 2008;27:4752. doi: 10.1038/onc.2008.111 https://www.nature.com/articles/onc2008111#supplementary-information. 18408759
45. Kotani A, Kakazu N, Tsuruyama T, Okazaki I-m, Muramatsu M, Kinoshita K, et al. Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proceedings of the National Academy of Sciences. 2007;104(5):1616–20. doi: 10.1073/pnas.0610732104 17251349
46. Rodriguez-Hernandez G, Opitz FV, Delgado P, Walter C, Alvarez-Prado AF, Gonzalez-Herrero I, et al. Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID. Nat Commun. 2019;10(1):5563. Epub 2019/12/06. doi: 10.1038/s41467-019-13570-y 31804490; PubMed Central PMCID: PMC6895129.
47. Okazaki I-m, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K, et al. Constitutive Expression of AID Leads to Tumorigenesis. The Journal of Experimental Medicine. 2003;197(9):1173–81. doi: 10.1084/jem.20030275 12732658
48. Rucci F, Cattaneo L, Marrella V, Sacco MG, Sobacchi C, Lucchini F, et al. Tissue-specific sensitivity to AID expression in transgenic mouse models. Gene. 2006;377:150–8. Epub 2006/06/22. doi: 10.1016/j.gene.2006.03.024 16787714.
49. Shen HM, Bozek G, Pinkert CA, McBride K, Wang L, Kenter A, et al. Expression of AID transgene is regulated in activated B cells but not in resting B cells and kidney. Mol Immunol. 2008;45(7):1883–92. Epub 2007/12/11. doi: 10.1016/j.molimm.2007.10.041 18067961; PubMed Central PMCID: PMC2376253.
50. Muto T, Okazaki I-m, Yamada S, Tanaka Y, Kinoshita K, Muramatsu M, et al. Negative regulation of activation-induced cytidine deaminase in B cells. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(8):2752–7. doi: 10.1073/pnas.0510970103 16477013
51. Robbiani DF, Bunting S, Feldhahn N, Bothmer A, Camps J, Deroubaix S, et al. AID Produces DNA Double-Strand Breaks in Non-Ig Genes and Mature B Cell Lymphomas with Reciprocal Chromosome Translocations. Molecular Cell. 2009;36:631–41. doi: 10.1016/j.molcel.2009.11.007 19941823
52. Pérez-García A, Pérez-Durán P, Wossning T, Sernandez IV, Mur SM, Cañamero M, et al. AID-expressing epithelium is protected from oncogenic transformation by an NKG2D surveillance pathway. EMBO Molecular Medicine. 2015;7(10):1327–36. doi: 10.15252/emmm.201505348 26282919
53. Rickert RC, Roes J, Rajewsky K. B lymphocyte-specific, Cre-mediated mutagenesis in mice. Nucleic Acids Res. 1997;25(6):1317–8. doi: 10.1093/nar/25.6.1317 9092650; PubMed Central PMCID: PMC146582.
54. Belver L, de Yébenes VG, Ramiro AR. MicroRNAs Prevent the Generation of Autoreactive Antibodies. Immunity. 2010;33(5):713–22. doi: 10.1016/j.immuni.2010.11.010 21093320
55. Hobeika E, Thiemann S, Storch B, Jumaa H, Nielsen PJ, Pelanda R, et al. Testing gene function early in the B cell lineage in mb1-cre mice. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(37):13789–94. Epub 08/29. doi: 10.1073/pnas.0605944103 16940357.
56. de Boer J, Williams A, Skavdis G, Harker N, Coles M, Tolaini M, et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur J Immunol. 2003;33(2):314–25. Epub 2003/01/28. doi: 10.1002/immu.200310005 12548562.
57. Casellas R, Basu U, Yewdell WT, Chaudhuri J, Robbiani DF, Di Noia JM. Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nat Rev Immunol. 2016;16(3):164–76. Epub 2016/02/24. doi: 10.1038/nri.2016.2 26898111; PubMed Central PMCID: PMC4871114.
58. Greaves M. Evolutionary determinants of cancer. Cancer Discov. 2015;5(8):806–20. doi: 10.1158/2159-8290.CD-15-0439 26193902; PubMed Central PMCID: PMC4539576.
59. McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27(1):15–26. doi: 10.1016/j.ccell.2014.12.001 25584892.
60. McGranahan N, Swanton C. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell. 2017;168(4):613–28. doi: 10.1016/j.cell.2017.01.018 28187284.
61. Miller CA, White BS, Dees ND, Griffith M, Welch JS, Griffith OL, et al. SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLoS Comput Biol. 2014;10(8):e1003665. doi: 10.1371/journal.pcbi.1003665 25102416; PubMed Central PMCID: PMC4125065.
62. Gronbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen MK, Hansen NE, et al. Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity. Blood. 1998;92(9):3018–24. Epub 1998/10/27. 9787134.
63. Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proceedings of the National Academy of Sciences. 2015;112(10):E1116–E25. doi: 10.1073/pnas.1501199112 25713363
64. Green MR. Chromatin modifying gene mutations in follicular lymphoma. Blood. 2018;131(6):595–604. doi: 10.1182/blood-2017-08-737361 29158360
65. Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Tamborero D, Schroeder MP, Jene-Sanz A, et al. IntOGen-mutations identifies cancer drivers across tumor types. Nat Methods. 2013;10(11):1081–2. doi: 10.1038/nmeth.2642 24037244; PubMed Central PMCID: PMC5758042.
66. Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, et al. The genetic landscape of mutations in Burkitt lymphoma. Nature Genetics. 2012;44(12):1321–5. doi: 10.1038/ng.2468 23143597
67. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proceedings of the National Academy of Sciences. 2012;109:3879–84. doi: 10.1073/pnas.1121343109 22343534
68. Miranda NFCCd, Georgiou K, Chen L, Wu C, Gao Z, Zaravinos A, et al. Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients. Blood. 2014;124:2544–53. doi: 10.1182/blood-2013-12-546309 25171927
69. Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood. 2013;122:1256–65. doi: 10.1182/blood-2013-02-483727 23699601
70. Okosun J, Bödör C, Wang J, Araf S, Yang C-Y, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genetics. 2014;46(2):176–81. doi: 10.1038/ng.2856 24362818
71. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences. 2013;110:1398–403. doi: 10.1073/pnas.1205299110 23292937
72. Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018;378(15):1396–407. Epub 2018/04/12. doi: 10.1056/NEJMoa1801445 29641966; PubMed Central PMCID: PMC6010183.
73. Pasqualucci L, Khiabanian H, Fangazio M, Vasishtha M, Messina M, Holmes AB, et al. Genetics of follicular lymphoma transformation. Cell Rep. 2014;6(1):130–40. Epub 2014/01/07. doi: 10.1016/j.celrep.2013.12.027 24388756; PubMed Central PMCID: PMC4100800.
74. Loeffler M, Kreuz M, Haake A, Hasenclever D, Trautmann H, Arnold C, et al. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia. 2015;29(2):456–63. Epub 2014/07/17. doi: 10.1038/leu.2014.209 25027518.
75. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr., Butel JS, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356(6366):215–21. Epub 1992/03/29. doi: 10.1038/356215a0 1552940.
76. Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, et al. Uracil-DNA Glycosylase (UNG)-Deficient Mice Reveal a Primary Role of the Enzyme during DNA Replication. Molecular Cell. 2000;5:1059–65. doi: 10.1016/s1097-2765(00)80271-3 10912000
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 12
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo
- Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies
- PEA15 loss of function and defective cerebral development in the domestic cat
- Precision medicine in cats—The right biomedical model may not be the mouse!
