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Chapter 20 : Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite

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Abstract:

Antigenic variation is of great importance for the success and survival of various pathogens ranging from trypanosomes to bacteria, fungi, and the focus of this paper, , the most virulent of the human malaria parasites ( ). For each pathogen, the pressure to diversify surface proteins exposed to the immune system is counterbalanced by the need to preserve function, which in the case of is the maintenance of binding capacity to receptors on vasculature endothelial cells ( ). Each pathogen has developed a systematic method to diversify surface proteins while balancing these strong but opposing selection pressures. This typically involves the generation of DNA sequence modifications to the genes that encode the surface proteins in ways that generate diversity without compromising function. These changes are created using the particular complement of DNA recombination and repair pathways present within the pathogen. Due to the critical nature of maintaining DNA integrity, DNA repair pathways are highly conserved across species from bacteria to mammals and components of most pathways can be readily identified in various organisms ( ), making DNA recombination/repair a subject of interest both for evolutionary biologists as well as for those interested in host–pathogen interactions.

Citation: Kirkman L, Deitsch K. 2015. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite , p 437-449. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0022-2014
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Figures

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Figure 1

Schematic representation of the life cycle highlighting major points of morphological transition and replication. (1) Asexual replication within the erythrocytes of the mammalian host. (2) Male and female gametocytes circulating within the blood stream of the mammalian host prior to being acquired by the mosquito vector during a blood meal. (3) Male and female parasites as they leave the red blood cells prior to fusion and sexual division. The “rounded up” female is shown on the left and the male undergoing exflagellation is shown on the right. (4) The motile ookinete that crosses the gut wall of the blood fed mosquito. (5) An oocyst that forms after the ookinete crosses the gut wall. The parasite undergoes numerous asexual divisions at this point, giving rise to thousands of sporozoites. (6) Sporozoites that infect the salivary glands of the mosquito and are injected into a mammalian host during a subsequent blood meal. They then travel to and invade cells within the liver. (7) A liver cell infected with asexually replicating parasites. These parasites leave the liver and infect circulating red blood cells, thus completing the cycle. Figure adapted with permission from reference .

Citation: Kirkman L, Deitsch K. 2015. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite , p 437-449. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0022-2014
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Figure 2

Structure and genomic arrangement of the gene family in . (A) Schematic showing the two exon structure of all genes. Note that the 5′ UTR, intron, exon 2 and 3′ UTR are all highly conserved (gray). The sequence of the 5′ UTR and upstream regulatory domains can be classified into three basic types called A, B and C. Exon 1 encodes the polymorphic portion of PfEMP1 and is arranged as an alternating series of highly diverse sequences separating regions of higher similarity. Overall the greatest degree of sequence diversity is found at the 3′ end of exon 1 as represented by the color gradient. Exon 2 encodes a highly conserved region of PfEMP1 that is not exposed to the immune system. (B) General chromosomal arrangement of genes, with type C genes typically found in tandem arrangement in the internal regions of the chromosomes while types A and B genes are located next to the telomere repeats. The telomeres are known to cluster into “bouquets” which align the genes in a way that is proposed to facilitate recombination and gene conversion events. (C) Illustration (left) showing the subnuclear localization of the telomere bouquets (yellow spots) that are found near the nuclear envelope within regions of dense heterochromatin (dark blue). Regions of less dense euchromatin are typically found near the center of the nucleus (light blue). Fluorescent hybridization showing the location of the gene clusters within the parasite’s nucleus. A probe that hybridizes to the conserved exon 2 of genes is shown in yellow while the nuclear DNA is stained with DAPI (4′,6-diamidino-2-phenylindole) and is shown in blue. Image in Fig. 2(B) modified with permission from reference . Image in Fig. 2(C) modified with permission from reference .

Citation: Kirkman L, Deitsch K. 2015. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite , p 437-449. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0022-2014
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Figure 3

Phylogenetic tree of the Apicomplexan lineage. The different colors highlight several groups of obligate, Apicomplexan parasites. The (orange) include parasites that cause malaria in humans ( and ), nonhuman primates () and rodents ( and ). The (green) are parasites transmitted by ticks that infect either red blood cells () or white blood cells ( and ). The (blue) are cyst forming parasites that do not undergo antigenic variation. The (purple) also form cysts and have a highly reduced genome. The ciliates, as exemplified by and , are nonparasitic, free living organisms. The ability of the organisms to utilize the C-NHEJ pathway for DSB repair is inferred by the presence or absence of proteins of the Ku family. Note that, of the Apicomplexans, only the have retained these genes within their genomes. The annotations numbers for Ku70/80 are given for both the and the Ciliates. The phylogenetic relationships are shown as described in reference .

Citation: Kirkman L, Deitsch K. 2015. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite , p 437-449. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0022-2014
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References

/content/book/10.1128/9781555819217.chap20
1. Deitsch KW,, Lukehart SA,, Stringer JR . 2009. Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7 : 493 503.[PubMed] [CrossRef]
2. Smith JD,, Deitsch KW, . 2012. Antigenic Variation, Adherence and Virulence, p 338 361. In Sibley LD,, Howlett BJ,, Heitman J (ed), Evolution of Virulence in Eukaryotic Microbes, Wiley-Blackwell, Hoboken, NJ.
3. Kass EM,, Jasin M . 2010. Collaboration and competition between DNA double-strand break repair pathways. FEBS Lett 584 : 3703 3708.[PubMed] [CrossRef]
4. Moynahan ME,, Jasin M . 2010. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11 : 196 207.[PubMed] [CrossRef]
5. Gill EE,, Becnel JJ,, Fast NM . 2008. ESTs from the microsporidian Edhazardia aedis. BMC Genomics 9 : 296. [PubMed] [CrossRef]
6. Lopez-Camarillo C,, Lopez-Casamichana M,, Weber C,, Guillen N,, Orozco E,, Marchat LA . 2009. DNA repair mechanisms in eukaryotes: Special focus in Entamoeba histolytica and related protozoan parasites. Infect, Genet Evol 9 : 1051 1056.[PubMed] [CrossRef]
7. Aravind L,, Iyer LM,, Wellems TE,, Miller LH . 2003. Plasmodium biology: Genomic gleanings. Cell 115 : 771 785.[PubMed] [CrossRef]
8. Smolarz B,, Wilczynski J,, Nowakowska D . 2014. DNA repair mechanisms and Toxoplasma gondii infection. Arch Microbiol 196 : 1 8.[PubMed] [CrossRef]
9. Machado CR,, Augusto-Pinto L,, McCulloch R,, Teixeira SM . 2006. DNA metabolism and genetic diversity in Trypanosomes. Mutat Res 612 : 40 57.[PubMed] [CrossRef]
10. Bhattacharyya MK,, Norris DE,, Kumar N . 2004. Molecular players of homologous recombination in protozoan parasites: implications for generating antigenic variation. Infect Genet Evol 4 : 91 98.[PubMed] [CrossRef]
11. Donelson JE . 2003. Antigenic variation and the African trypanosome genome. Acta Trop 85 : 391 404.[PubMed] [CrossRef]
12. David PH,, Hommel M,, Miller LH,, Udeinya IJ,, Oligino LD . 1983. Parasite sequestration in Plasmodium falciparum malaria: Spleen and antibody modulation of cytoadherence of infected erythrocytes. Proc Natl Acad Sci U S A 80 : 5075 5079.[PubMed] [CrossRef]
13. Scherf A,, Lopez-Rubio JJ,, Riviere L . 2008. Antigenic variation in Plasmodium falciparum. Annu Rev Microbiol 62 : 445 470.[PubMed] [CrossRef]
14. Miller LH,, Baruch DI,, Marsh K,, Doumbo OK . 2002. The pathogenic basis of malaria. Nature 415 : 673 679.[PubMed] [CrossRef]
15. Gardner MJ,, Hall N,, Fung E,, White O,, Berriman M,, Hyman RW,, Carlton JM,, Pain A,, Nelson KE,, Bowman S,, Paulsen IT,, James K,, Eisen JA,, Rutherford K,, Salzberg SL,, Craig A,, Kyes S,, Chan MS,, Nene V,, Shallom SJ,, Suh B,, Peterson J,, Angiuoli S,, Pertea M,, Allen J,, Selengut J,, Haft D,, Mather MW,, Vaidya AB,, Martin DM,, Fairlamb AH,, Fraunholz MJ,, Roos DS,, Ralph SA,, McFadden GI,, Cummings LM,, Subramanian GM,, Mungall C,, Venter JC,, Carucci DJ,, Hoffman SL,, Newbold C,, Davis RW,, Fraser CM,, Barrell B . 2002. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419 : 498 511.[PubMed] [CrossRef]
16. Su X,, Heatwole VM,, Wertheimer SP,, Guinet F,, Herrfeldt JV,, Peterson DS,, Ravetch JV,, Wellems TE . 1995. A large and diverse gene family ( var) encodes 200–350 kD proteins implicated in the antigenic variation and cytoadherence of Plasmodium falciparum-infected erythrocytes. Cell 82 : 89 100.[PubMed] [CrossRef]
17. Baruch DI,, Pasloske BL,, Singh HB,, Bi X,, Ma XC,, Feldman M,, Taraschi TF,, Howard RJ . 1995. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82 : 77 87.[PubMed] [CrossRef]
18. Smith JD,, Chitnis CE,, Craig AG,, Roberts DJ,, Hudson-Taylor DE,, Peterson DS,, Pinches R,, Newbold CI,, Miller LH . 1995. Switches in expression of Plasmodium falciparumvar genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82 : 101 110.[PubMed] [CrossRef]
19. Cheng Q,, Cloonan N,, Fischer K,, Thompson J,, Waine G,, Lanzer M,, Saul A . 1998. Stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens. Mol Biochem Parasitol 97 : 161 176.[PubMed] [CrossRef]
20. Lavazec C,, Sanyal S,, Templeton TJ . 2006. Hypervariability within the Rifin, Stevor and Pfmc-2TM superfamilies in Plasmodium falciparum. Nucleic Acids Res 34 : 6696 6707.[PubMed] [CrossRef]
21. Sam-Yellowe TY,, Florens L,, Johnson JR,, Wang T,, Drazba JA,, Le Roch KG,, Zhou Y,, Batalov S,, Carucci DJ,, Winzeler EA,, Yates JR III . 2004. A Plasmodium gene family encoding Maurer’s cleft membrane proteins: structural properties and expression profiling. Genome Res 14 : 1052 1059.[PubMed] [CrossRef]
22. Kraemer SM,, Smith JD . 2003. Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family. Mol Microbiol 50 : 1527 1538.[PubMed] [CrossRef]
23. Lavstsen T,, Salanti A,, Jensen ATR,, Arnot DE,, Theander TG . 2003. Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions. Malar J 2 : 27. [PubMed] [CrossRef]
24. Rottmann M,, Lavstsen T,, Mugasa JP,, Kaestli M,, Jensen AT,, Muller D,, Theander T,, Beck HP . 2006. Differential expression of var gene groups is associated with morbidity caused by Plasmodium falciparum infection in Tanzanian children. Infect Immun 74 : 3904 3911.[PubMed] [CrossRef]
25. Falk N,, Kaestli M,, Qi W,, Ott M,, Baea K,, Cortes A,, Beck HP . 2009. Analysis of Plasmodium falciparum var genes expressed in children from Papua New Guinea. J Infect Dis 200 : 347 356.[PubMed] [CrossRef]
26. Kaestli M,, Cockburn IA,, Cortes A,, Baea K,, Rowe JA,, Beck HP . 2006. Virulence of malaria is associated with differential expression of Plasmodium falciparum var gene subgroups in a case-control study. J Infect Dis 193 : 1567 1574.[PubMed] [CrossRef]
27. Lavstsen T,, Turner L,, Saguti F,, Magistrado P,, Rask TS,, Jespersen JS,, Wang CW,, Berger SS,, Baraka V,, Marquard AM,, Sequin-Orlando A,, Willerslev E,, Gilbert MTP,, Lusingu J,, Theander TG . 2012. P. falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proc Natl Acad Sci U S A 109 : E1791 1800.[PubMed] [CrossRef]
28. Avril M,, Tripathi AK,, Brazier AJ,, Andisi C,, Janes JH,, Soma VL,, Sullivan DJ,, Bull PC,, Stins MF,, Smith JD . 2012. A restricted subset of var genes mediates adherence of Plasmodium falciparum infected erythrocytes to brain endothelial cells. Proc Natl Acad Sci U S A 109 : E1782 1790.[PubMed] [CrossRef]
29. Claessens A,, Adams Y,, Ghumra A,, Lindergard G,, Buchan CC,, Andisi C,, Bull PC,, Mok SC,, Gupta AP,, Wang CW,, Turner L,, Arman M,, Raza A,, Bozdech Z,, Rowe JA . 2012. A subset of Group A-like var genes encode the malaria parasite ligands for binding to human brain endothelial cells. Proc Natl Acad Sci U S A 109 : E1772 1781.[PubMed] [CrossRef]
30. Scherf A,, Hernandez-Rivas R,, Buffet P,, Bottius E,, Benatar C,, Pouvelle B,, Gysin J,, Lanzer M . 1998. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum . EMBO J 17 : 5418 5426.[PubMed] [CrossRef]
31. Allred DR,, Carlton JM,, Satcher RL,, Long JA,, Brown WC,, Patterson PE,, O’Connor RM,, Stroup SE . 2000. The ves multigene family of B. bovis encodes components of rapid antigenic variation at the infected erythrocyte surface. Mol Cell 5 : 153 162.[PubMed] [CrossRef]
32. al Khedery B,, Allred DR . 2006. Antigenic variation in Babesia bovis occurs through segmental gene conversion of the ves multigene family, within a bidirectional locus of active transcription. Mol Microbiol 59 : 402 414.[PubMed] [CrossRef]
33. Pays E . 2005. Regulation of antigen gene expression in Trypanosoma brucei. Trends Parasitol 21 : 517 520.[PubMed] [CrossRef]
34. Dzikowski R,, Frank M,, Deitsch K . 2006. Mutually Exclusive Expression of Virulence Genes by Malaria Parasites Is Regulated Independently of Antigen Production. PLoS Pathog 2 : e22. [PubMed] [CrossRef]
35. Voss TS,, Healer J,, Marty AJ,, Duffy MF,, Thompson JK,, Beeson JG,, Reeder JC,, Crabb BS,, Cowman AF . 2006. A var gene promoter controls allelic exclusion of virulence genes in Plasmodium falciparum malaria. Nature 439 : 1004 1008.[PubMed]
36. Lopez-Rubio JJ,, Riviere L,, Scherf A . 2007. Shared epigenetic mechanisms control virulence factors in protozoan parasites. Curr Opin Microbiol 10 : 560 568.[PubMed] [CrossRef]
37. Barry AE,, Leliwa-Sytek A,, Tavul L,, Imrie H,, Migot-Nabias F,, Brown SM,, McVean GA,, Day KP . 2007. Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum. PLoS Pathog 3 : e34. [PubMed] [CrossRef]
38. Albrecht L,, Castineiras C,, Carvalho BO,, Ladeia-Andrade S,, Santos dS,, Hoffmann EH,, dalla Martha RC,, Costa FT,, Wunderlich G . 2010. The South American Plasmodium falciparum var gene repertoire is limited, highly shared and possibly lacks several antigenic types. Gene 453 : 37 44.[PubMed] [CrossRef]
39. Ord RL,, Tami A,, Sutherland CJ . 2008. ama1 genes of sympatric Plasmodium vivax and P. falciparum from Venezuela differ significantly in genetic diversity and recombination frequency. PLoS One 3 : e3366. [PubMed] [CrossRef]
40. Mu J,, Awadalla P,, Duan J,, McGee KM,, Joy DA,, McVean GA,, Su XZ . 2005. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol 3 : e335. [PubMed] [CrossRef]
41. Dharia NV,, Plouffe D,, Bopp SE,, Gonzalez-Paez GE,, Lucas C,, Salas C,, Soberon V,, Bursulaya B,, Kochel TJ,, Bacon DJ,, Winzeler EA . 2010. Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites. Genome Res 20 : 1534 1544.[PubMed] [CrossRef]
42. Kraemer SM,, Kyes SA,, Aggarwal G,, Springer AL,, Nelson SO,, Christodoulou Z,, Smith LM,, Wang W,, Levin E,, Newbold CI,, Myler PJ,, Smith JD . 2007. Patterns of gene recombination shape var gene repertoires in Plasmodium falciparum: comparisons of geographically diverse isolates. BMC Genomics 8 : 45. [PubMed] [CrossRef]
43. Bull PC,, Buckee CO,, Kyes S,, Kortok MM,, Thathy V,, Guyah B,, Stoute JA,, Newbold CI,, Marsh K . 2008. Plasmodium falciparum antigenic variation. Mapping mosaic var gene sequences onto a network of shared, highly polymorphic sequence blocks. Mol Microbiol 68 : 1519 1534.[PubMed] [CrossRef]
44. Therizols P,, Fairhead C,, Cabal GG,, Genovesio A,, Olivo-Marin JC,, Dujon B,, Fabre E . 2006. Telomere tethering at the nuclear periphery is essential for efficient DNA double strand break repair in subtelomeric region. J Cell Biol 172 : 189 199.[PubMed] [CrossRef]
45. Freitas-Junior LH,, Bottius E,, Pirrit LA,, Deitsch KW,, Scheidig C,, Guinet F,, Nehrbass U,, Wellems TE,, Scherf A . 2000. Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407 : 1018 1022.[PubMed] [CrossRef]
46. Sander AF,, Lavstsen T,, Rask TS,, Lisby M,, Salanti A,, Fordyce SL,, Jespersen JS,, Carter R,, Deitsch KW,, Theander TG,, Pedersen AG,, Arnot DE . 2014. DNA secondary structures are associated with recombination in major Plasmodium falciparum variable surface antigen gene families. Nucleic Acids Res 42 : 2270 2281.[PubMed] [CrossRef]
47. Becker K,, Tilley L,, Vennerstrom JL,, Roberts D,, Rogerson S,, Ginsburg H . 2004. Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Int J Parasitol 34 : 163 189.[PubMed] [CrossRef]
48. Prada J,, Kremsner PG . 1995. Enhanced production of reactive nitrogen intermediates in human and murine malaria. Parasitol Today 11 : 409 410.[CrossRef]
49. Barzilai A,, Yamamoto K . 2004. DNA damage responses to oxidative stress. DNA Repair 3 : 1109 1115.[PubMed] [CrossRef]
50. Mattei D,, Scherf A . 1994. Subtelomeric chromosome instability in Plasmodium falciparum: short telomere-like sequence motifs found frequently at healed chromosome breakpoints. Mutat Res 324 : 115 120.[PubMed] [CrossRef]
51. Houze S,, Hubert V,, Le Pessec G,, Le Bras J,, Clain J . 2011. Combined deletions of pfhrp2 and pfhrp3 genes result in Plasmodium falciparum malaria false-negative rapid diagnostic test. J Clin Microbiol 49 : 2694 2696.[PubMed] [CrossRef]
52. Koita OA,, Doumbo OK,, Ouattara A,, Tall LK,, Konare A,, Diakite M,, Diallo M,, Sagara I,, Masinde GL,, Doumbo SN,, Dolo A,, Tounkara A,, Traore I,, Krogstad DJ . 2012. False-negative rapid diagnostic tests for malaria and deletion of the histidine-rich repeat region of the hrp2 gene. Am J Trop Med Hyg 86 : 194 198.[PubMed] [CrossRef]
53. Maltha J,, Gamboa D,, Bendezu J,, Sanchez L,, Cnops L,, Gillet P,, Jacobs J . 2012. Rapid diagnostic tests for malaria diagnosis in the Peruvian Amazon: impact of pfhrp2 gene deletions and cross-reactions. PLoS One 7 : e43094. [PubMed] [CrossRef]
54. Kumar N,, Pande V,, Bhatt RM,, Shah NK,, Mishra N,, Srivastava B,, Valecha N,, Anvikar AR . 2013. Genetic deletion of HRP2 and HRP3 in Indian Plasmodium falciparum population and false negative malaria rapid diagnostic test. Acta Trop 125 : 119 121.[PubMed] [CrossRef]
55. Bopp SE,, Manary MJ,, Bright AT,, Johnston GL,, Dharia NV,, Luna FL,, McCormack S,, Plouffe D,, McNamara CW,, Walker JR,, Fidock DA,, Denchi EL,, Winzeler EA . 2013. Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families. PLoS Genet 9 : e1003293. [PubMed] [CrossRef]
56. Frank M,, Kirkman L,, Costantini D,, Sanyal S,, Lavazec C,, Templeton TJ,, Deitsch KW . 2008. Frequent recombination events generate diversity within the multi-copy variant antigen gene families of Plasmodium falciparum. Int J Parasitol 38 : 1099 1109.[PubMed] [CrossRef]
57. Hefferin ML,, Tomkinson AE . 2005. Mechanism of DNA double-strand break repair by non-homologous end joining. DNA Repair 4 : 639 648.[PubMed] [CrossRef]
58. Johnson RD,, Jasin M . 2001. Double-strand-break-induced homologous recombination in mammalian cells. Biochem Soc Trans 29 : 196 201.[PubMed] [CrossRef]
59. Mladenov E,, Iliakis G . 2011. Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways. Mutat Res 711 : 61 72.[PubMed] [CrossRef]
60. Fattah F,, Lee EH,, Weisensel N,, Wang Y,, Lichter N,, Hendrickson EA . 2010. Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. PLoS Genet 6 : e1000855. [PubMed] [CrossRef]
61. Yu AM,, McVey M . 2010. Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res 38 : 5706 5717.[PubMed] [CrossRef]
62. Gill EE,, Fast NM . 2007. Stripped-down DNA repair in a highly reduced parasite. BMC Mol Biol 8 : 24. [PubMed] [CrossRef]
63. Burton P,, McBride DJ,, Wilkes JM,, Barry JD,, McCulloch R . 2007. Ku heterodimer-independent end joining in Trypanosoma brucei cell extracts relies upon sequence microhomology. Eukaryotic Cell 6 : 1773 1781.[PubMed] [CrossRef]
64. Conway C,, McCulloch R,, Ginger ML,, Robinson NP,, Browitt A,, Barry JD . 2002. Ku is important for telomere maintenance, but not for differential expression of telomeric VSG genes, in African trypanosomes. J Biol Chem 277 : 21269 21277.[PubMed] [CrossRef]
65. Glover L,, Jun J,, Horn D . 2011. Microhomology-mediated deletion and gene conversion in African trypanosomes. Nucleic Acids Res 39 : 1372 1380.[PubMed] [CrossRef]
66. Barry JD,, Marcello L,, Morrison LJ,, Read AF,, Lythgoe K,, Jones N,, Carrington M,, Blandin G,, Bohme U,, Caler E,, Hertz-Fowler C,, Renauld H,, El Sayed N,, Berriman M .. 2005. What the genome sequence is revealing about trypanosome antigenic variation. Biochem Soc Trans 33 : 986 989.[PubMed] [CrossRef]
67. Kirkman LA,, Lawrence EA,, Deitsch KW . 2014. Malaria parasites utilize both homologous recombination and alternative end joining pathways to maintain genome integrity. Nucleic Acids Res 42 : 370 379.[PubMed] [CrossRef]
68. Fox BA,, Falla A,, Rommereim LM,, Tomita T,, Gigley JP,, Mercier C,, Cesbron-Delauw MF,, Weiss LM,, Bzik DJ . 2011. Type II Toxoplasma gondii KU80 knockout strains enable functional analysis of genes required for cyst development and latent infection. Eukaryotic Cell 10 : 1193 1206.[PubMed] [CrossRef]
69. Fox BA,, Ristuccia JG,, Gigley JP,, Bzik DJ . 2009. Efficient gene replacements in Toxoplasma gondii strains deficient for nonhomologous end joining. Eukaryotic Cell 8 : 520 529.[PubMed] [CrossRef]
70. Huynh MH,, Carruthers VB . 2009. Tagging of endogenous genes in a Toxoplasma gondii strain lacking Ku80. Eukaryotic Cell 8 : 530 539.[PubMed] [CrossRef]
71. Aravind L,, Koonin EV . 2001. Prokaryotic homologs of the eukaryotic DNA-end-binding protein Ku, novel domains in the Ku protein and prediction of a prokaryotic double-strand break repair system. Genome Res 11 : 1365 1374.[PubMed] [CrossRef]
72. Abrahamsen MS,, Templeton TJ,, Enomoto S,, Abrahante JE,, Zhu G,, Lancto CA,, Deng M,, Liu C,, Widmer G,, Tzipori S,, Buck GA,, Xu P,, Bankier AT,, Dear PH,, Konfortov BA,, Spriggs HF,, Iyer L,, Anantharaman V,, Aravind L,, Kapur V . 2004. Complete genome sequence of the apicomplexan, Cryptosporidium parvum. Science 304 : 441 445.[PubMed] [CrossRef]
73. Chookajorn T,, Dzikowski R,, Frank M,, Li F,, Jiwani AZ,, Hartl DL,, Deitsch KW . 2007. Epigenetic memory at malaria virulence genes. Proc Natl Acad Sci U S A 104 : 899 902.[PubMed] [CrossRef]
74. Lopez-Rubio JJ,, Gontijo AM,, Nunes MC,, Issar N,, Hernandez RR,, Scherf A . 2007. 5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites. Mol Microbiol 66 : 1296 1305.[PubMed]
75. Jiang L,, Mu J,, Zhang Q,, Ni T,, Srinivasan P,, Rayavara K,, Yang W,, Turner L,, Lavstsen T,, Theander TG,, Peng W,, Wei G,, Jing Q,, Wakabayashi Y,, Bansal A,, Luo Y,, Ribeiro JM,, Scherf A,, Aravind L,, Zhu J,, Zhao K,, Miller LH . 2013. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum. Nature 499 : 223 227.[PubMed] [CrossRef]
76. Ukaegbu UE,, Kishore SP,, Kwiatkowski DL,, Pandarinath C,, Dahan-Pasternak N,, Dzikowski R,, Deitsch KW . 2014. Recruitment of PfSET2 by RNA polymerase II to variant antigen encoding loci contributes to antigenic variation in P. falciparum. PLoS Pathog 10 : e1003854. [PubMed] [CrossRef]
77. Lopez-Rubio JJ,, Mancio-Silva L,, Scherf A . 2009. Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites. Cell Host Microbe 5 : 179 190.[PubMed] [CrossRef]
78. Flueck C,, Bartfai R,, Volz J,, Niederwieser I,, Salcedo-Amaya AM,, Alako BT,, Ehlgen F,, Ralph SA,, Cowman AF,, Bozdech Z,, Stunnenberg HG,, Voss TS . 2009. Plasmodium falciparum heterochromatin protein 1 marks genomic loci linked to phenotypic variation of exported virulence factors. PLoS Pathog 5 : e1000569. [PubMed] [CrossRef]
79. Marty AJ,, Thompson JK,, Duffy MF,, Voss TS,, Cowman AF,, Crabb BS . 2006. Evidence that Plasmodium falciparum chromosome end clusters are cross-linked by protein and are the sites of both virulence gene silencing and activation. Mol Microbiol 62 : 72 83.[PubMed] [CrossRef]
80. Figueiredo LM,, Freitas-Junior LH,, Bottius E,, Olivo-Marin JC,, Scherf A . 2002. A central role for Plasmodium falciparum subtelomeric regions in spatial positioning and telomere length regulation. EMBO J 21 : 815 824.[PubMed] [CrossRef]
81. Goodarzi AA,, Jeggo P,, Lobrich M . 2010. The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax. DNA Repair 9 : 1273 1282.[PubMed] [CrossRef]
82. Miller D,, Reynolds GE,, Mejia R,, Stark JM,, Murnane JP . 2011. Subtelomeric regions in mammalian cells are deficient in DNA double-strand break repair. DNA Repair 10 : 536 544.[PubMed] [CrossRef]
83. Hakimi MA,, Deitsch KW . 2007. Epigenetics in Apicomplexa: control of gene expression during cell cycle progression, differentiation and antigenic variation. Curr Opin Microbiol 10 : 357 362.[PubMed] [CrossRef]
84. Kirkman LA,, Deitsch KW . 2012. Antigenic variation and the generation of diversity in malaria parasites. Curr Opin Microbiol 15 : 456 462.[PubMed] [CrossRef]
85. Dzikowski R,, Templeton TJ,, Deitsch K . 2006. Variant antigen gene expression in malaria. Cell Microbiol 8 : 1371 1381.[PubMed] [CrossRef]
86. DeBarry J,, Fatumo S,, Kissinger J, . 2013. The apicomplexan genomic landscape: the evolutionary context of Plasmodium, p 17 35. In Carlton JM,, Perkins SL,, Deitsch KW (ed), Malaria Parasites: Comparative Genomics, Evolution and Molecular Biology. Caister Academic Press, Norfolk, UK.

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