Complex chromosome aberrations (any exchange involving three or more breaks in two or more chromosomes) are effectively induced in peripheral blood lymphocytes (PBL) after exposure to low doses (mostly single particles) of densely ionising high-linear energy transfer (LET) α-particle radiation. The complexity, when observed by multiplex fluorescence in situ hybridisation (m-FISH), shows that commonly four but up to eight different chromosomes can be involved in each rearrangement. Given the territorial organisation of chromosomes in interphase and that only a very small fraction of the nucleus is irradiated by each α-particle traversal, the aim of this study is to address how aberrations of such complexity can be formed. To do this, we applied theoretical “cycle” analyses using m-FISH paint detail of PBL in their first cell division after exposure to high-LET α-particles. In brief, “cycle” analysis deconstructs the aberration “observed” by m-FISH to make predictions as to how it could have been formed in interphase. We propose from this that individual high-LET α-particle-induced complex aberrations may be formed by the misrepair of damaged chromatin in single physical “sites” within the nucleus, where each “site” is consistent with an “area” corresponding to the interface of two to three different chromosome territories. Limited migration of damaged chromatin is “allowed” within this “area”. Complex aberrations of increased size, reflecting the path of α-particle nuclear intersection, are formed through the sequential linking of these individual sites by the involvement of common chromosomes.   

1.
Anderson RM, Marsden SJ, Wright EG, Kadhim MA, Goodhead DT, Griffin CS: Complex chromosome aberrations in peripheral blood lymphocytes as a potential biomarker of exposure to high-LET alpha-particles. Int J Radiat Biol 76:31–42 (2000).
2.
Anderson RM, Stevens DL, Goodhead DT: M-FISH analysis shows that complex chromosome aberrations induced by alpha-particle tracks are cumulative products of localized rearrangements. Proc Natl Acad Sci USA 99:12167–12172 (2002).
3.
Arsuaga J, Greulich-Bode KM, Vazquez M, Bruckner M, Hahnfeldt P, Brenner DJ, Sachs R, Hlatky L: Chromosome spatial clustering inferred from radiogenic aberrations. Int J Radiat Biol 80:507–515 (2004).
4.
Aten JA, Stap J, Krawczyk PM, van Oven CH, Hoebe RA, Essers J, Kanaar R: Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303:92–95 (2004).
5.
Bender MA, Griggs HG, Bedford JS: Mechanisms of chromosomal aberration production. 3. Chemicals and ionizing radiation. Mutat Res 23:197–212 (1974).
6.
Boei JJ, Vermeulen S, Moser J, Mullenders LH, Natarajan AT: Intrachanges as part of complex chromosome-type exchange aberrations. Mutat Res 504:47–55 (2002).
7.
Bornfleth H, Edelmann P, Zink D, Cremer T, Cremer C: Quantitative motion analysis of subchromosomal foci in living cells using four-dimensional microscopy. Biophys J 77:2871–2886 (1999).
8.
Boyle S, Gilchrist S, Bridger JM, Mahy NL, Ellis JA, Bickmore WA: The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. Hum Mol Genet 10:211–219 (2001).
9.
Brown JM, Evans JW, Kovacs MS: Mechanism of chromosome exchange formation in human fibroblasts: insights from “chromosome painting“. Environ Mol Mutagen 22:218–224 (1993).
10.
Bryant PE: Enzymatic restriction of mammalian cell DNA using Pvu II and Bam H1: evidence for the double-strand break origin of chromosomal aberrations. Int J Radiat Biol Relat Stud Phys Chem Med 46:57–65 (1984).
11.
Cafourkova A, Lukasova E, Kozubek S, Kozubek M, Govorun RD, Koutna I, Bartova E, Skalnikova M, Jirsova P, Pasekova R, Krasavin EA: Exchange aberrations among 11 chromosomes of human lymphocytes induced by gamma-rays. Int J Radiat Biol 77:419–429 (2001).
12.
Chadwick KH, Leenhouts HP: The rejoining of DNA double-strand breaks and a model for the formation of chromosomal rearrangements. Int J Radiat Biol Relat Stud Phys Chem Med 33:517–529 (1978).
13.
Cigarran S, Barrios L, Barquinero JF, Caballin MR, Ribas M, Egozcue J: Relationship between the DNA content of human chromosomes and their involvement in radiation-induced structural aberrations, analysed by painting. Intl J Rad Biol 74:449–455 (1998).
14.
Cornforth MN: Analyzing radiation-induced complex chromosome rearrangements by combinatorial painting. Radiat Res 155:643–659 (2001).
15.
Cornforth MN, Bedford JS: X-ray-induced breakage and rejoining of human interphase chromosomes. Science 222:1141–1143 (1983).
16.
Cornforth MN, Greulich-Bode KM, Loucas BD, Arsuaga J, Vazquez M, Sachs RK, Bruckner M, Molls M, Hahnfeldt P, Hlatky L, Brenner DJ: Chromosomes are predominantly located randomly with respect to each other in interphase human cells. J Cell Biol 159:237–244 (2002).
17.
Cremer T, Cremer C: Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Genet 2:292–301 (2001).
18.
Cremer C, Munkel C, Granzow M, Jauch A, Dietzel S, Eils R, Guan XY, Meltzer PS, Trent JM, Langowski J, Cremer T: Nuclear architecture and the induction of chromosomal aberrations. Mutat Res 366:97–116 (1996).
19.
De Braekeleer M, Smith B: Two methods for measuring the non-randomness of chromosome abnormalities. Ann Hum Genet 52:63–67 (1988).
20.
Edelmann P, Bornfleth H, Zink D, Cremer T, Cremer C: Morphology and dynamics of chromosome territories in living cells. Biochim Biophys Acta 1551:M29–39 (2001).
21.
Edwards AA, Savage JR: Is there a simple answer to the origin of complex chromosome exchanges? Int J Radiat Biol 75:19–22 (1999).
22.
Featherstone C, Jackson SP: Ku, a DNA repair protein with multiple cellular functions? Mutat Res 434:3–15 (1999).
23.
Figgitt M, Savage JRK: Interphase chromosome domain re-organization following irradiation. Int J Radiat Biol 75:811–817 (1999).
24.
Goodhead DT: Track structure considerations in low-dose and low-dose rate effects of ionizing-radiation. Adv Radiat Biol 16:7–44 (1992).
25.
Goodhead DT, Bance DA, Stretch A, Wilkinson RE: A versatile Pu-238 irradiator for radiobiological studies with alpha-particles. Int J Radiat Biol 59:195–210 (1991).
26.
Greinert R, Volkmer B, Virsik-Peuckert RP, Harder D: Comparative study of the repair kinetics of chromosomal aberrations and DNA strand breaks in proliferating and quiescent CHO cells. Int J Radiat Biol 70:33–43 (1996).
27.
Griffin CS, Marsden SJ, Stevens DL, Simpson P, Savage JR: Frequencies of complex chromosome exchange aberrations induced by 238Pu alpha-particles and detected by fluorescence in situ hybridization using single chromosome-specific probes. Int J Radiat Biol 67:431–439 (1995).
28.
Griffin CS, Hill MA, Papworth DG, Townsend KMS, Savage JRK, Goodhead DT: Effectiveness of 0.28 keV carbon K ultrasoft X-rays at producing simple and complex chromosome exchanges in human fibroblasts in vitro detected using FISH. Int J Radiat Biol 73:591–598 (1998).
29.
Horstmann M, Durante M, Obe G: Distribution of breakpoints and fragment sizes in human chromosome 5 after heavy-ion bombardment. Int J Radiat Biol 80:437–443 (2004).
30.
Johannes C, Horstmann M, Durante M, Chudoba I, Obe G: Chromosome intrachanges and interchanges detected by multicolor banding in lymphocytes: searching for clastogen signatures in the human genome. Radiat Res 161:540–548 (2004).
31.
Johnson KL, Brenner DJ, Nath J, Tucker JD, Geard CR: Radiation-induced breakpoint misrejoining in human chromosomes: random or non-random? Int J Radiat Biol 75:131–141 (1999).
32.
Kuhne M, Rothkamm K, Lobrich M: Physical and biological parameters affecting DNA double strand break misrejoining in mammalian cells. Radiat Prot Dosim 99:129–132 (2002).
33.
Loucas BD, Cornforth MN: Complex chromosome exchanges induced by gamma rays in human lymphocytes: an mFISH study. Radiat Res 155:660–671 (2001).
34.
Loucas BD, Eberle R, Bailey SM, Cornforth MN: Influence of dose rate on the induction of simple and complex chromosome exchanges by gamma rays. Radiat Res 162:339–349 (2004).
35.
Marshall WF, Straight A, Marko JF, Swedlow J, Dernburg A, Belmont A, Murray AW, Agard DA, Sedat JW: Interphase chromosomes undergo constrained diffusional motion in living cells. Curr Biol 7:930–939 (1997).
36.
Masuzawa N, Urata Y, Yagi K, Ashihara T: Constrained, random and independent motion of Texas-red-labeled chromatin in living interphase PtK2 cells. Acta Histochem Cytochem 33:419–427 (2000).
37.
Moquet JE, Fernandez JL, Edwards AA, Lloyd DC: Lymphocyte chromosomal aberrations and their complexity induced in vitro by plutonium-239 alpha-particles and detected by FISH. Cell Mol Biol 47:549–556 (2001).
38.
Natarajan AT, Zwanenburg TS: Mechanisms for chromosomal aberrations in mammalian cells. Mutat Res 95:1–6 (1982).
39.
Obe G, Pfeiffer P, Savage JR, Johannes C, Goedecke W, Jeppesen P, Natarajan AT, Martinez-Lopez W, Folle GA, Drets ME: Chromosomal aberrations: formation, identification and distribution. Mutat Res 504:17–36 (2002).
40.
Ostashevsky JY: Higher-order structure of interphase chromosomes and radiation-induced chromosomal exchange aberrations. Int J Radiat Biol 76:1179–1187 (2000).
41.
Parada L, Misteli T: Chromosome positioning in the interphase nucleus. Trends Cell Biol 12:425–432 (2002).
42.
Pastwa E, Neumann RD, Mezhevaya K, Winters TA: Repair of radiation-induced DNA double-strand breaks is dependent upon radiation quality and the structural complexity of double-strand breaks. Radiat Res 159:251–261 (2003).
43.
Rothkamm K, Kuhne M, Jeggo PA, Lobrich M: Radiation-induced genomic rearrangements formed by nonhomologous end-joining of DNA double-strand breaks. Cancer Res 61:3886–3893 (2001).
44.
Sachs RK, Chen AM, Brenner DJ: Review: proximity effects in the production of chromosome aberrations by ionizing radiation. Int J Radiat Biol 71:1–19 (1997).
45.
Sachs RK, Chen AM, Simpson PJ, Hlatky LR, Hahnfeldt P, Savage JR: Clustering of radiation-produced breaks along chromosomes: modelling the effects on chromosome aberrations. Int J Radiat Biol 75:657–672 (1999).
46.
Savage JR: Interchange and intra-nuclear architecture. Environ Mol Mutagen 22:234–244 (1993).
47.
Savage JR: Insight into sites. Mutat Res 366:81–95 (1996).
48.
Savage JR: Cancer. Proximity matters. Science 290:62–63 (2000).
49.
Savage JR: Reflections and meditations upon complex chromosomal exchanges. Mutat Res 512:93–109 (2002).
50.
Savage JR, Papworth DG: The relationship of radiation-induced dicentric yield to chromosome arm number. Mutat Res 19:139–143 (1973).
51.
Savage JR, Simpson PJ: FISH “painting” patterns resulting from complex exchanges. Mutat Res 312:51–60 (1994).
52.
Sax K: Chromosome aberrations induced by X-rays. Genetics 23: 494–516 (1938).
53.
Simpson PJ, Savage JR: Detecting “hidden” exchange events within X-ray-induced aberrations using multicolour chromosome paints. Chromosome Res 3:69–72 (1995).
54.
Singleton BK, Griffin CS, Thacker J: Clustered DNA damage leads to complex genetic changes in irradiated human cells. Cancer Res 62:6263–6269 (2002).
55.
Sun HB, Shen J, Yokota H: Size-dependent positioning of human chromosomes in interphase nuclei. Biophys J 79:184–190 (2000).
56.
Tarone RE: Testing for non-randomness of events in sparse data situations. Ann Hum Genet 53:381–387 (1989).
57.
Visser AE, Aten JA: Chromosomes as well as chromosomal subdomains constitute distinct units in interphase nuclei. J Cell Sci 112:3353–3360 (1999).
58.
Visser AE, Jaunin F, Fakan S, Aten JA: High resolution analysis of interphase chromosome domains. J Cell Sci 113:2585–2593 (2000).
59.
Wang H, Zeng ZC, Bui TA, Sonoda E, Takata M, Takeda S, Iliakis G: Efficient rejoining of radiation-induced DNA double-strand breaks in vertebrate cells deficient in genes of the RAD52 epistasis group. Oncogene 20:2212–2224 (2001).
60.
Wu H, Durante M, Lucas JN: Relationship between radiation-induced aberrations in individual chromosomes and their DNA content: effects of interaction distance. Int J Radiat Biol 77:781–786 (2001).
61.
Zink D, Cremer T, Saffrich R, Fischer R, Trendelenburg MF, Ansorge W, Stelzer EH: Structure and dynamics of human interphase chromosome territories in vivo. Hum Genet 102:241–251 (1998).
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