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THE L5178Y SUBLINES: a SUMMARY of 40 YEAR STUDIES in WARSAW Irena Szumiel

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THE L5178Y SUBLINES: a SUMMARY of 40 YEAR STUDIES in WARSAW Irena Szumiel ISSN 1425-7351 PL0601824 RAPORTY IChTJ. SERIA B nr 2/2005 THE L5178Y SUBLINES: A SUMMARY OF 40 YEAR STUDIES IN WARSAW Irena Szumiel INSTYTUT CHEMII I TECHNIKI JĄDROWEJ INSTITUTE OF NUCLEAR CHEMISTRY AND TECHNOLOGY RAPORTY IChTJ. SERIA B nr 2/2005 THE L5178Y SUBLINES: A SUMMARY OF 40 YEAR STUDIES IN WARSAW Irena Szumiel Warszawa 2005 AUTHOR Irena Szumiel Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology This report is an extended version of the paper: " 'The L5178Y sublines: a look back from 40 years. 1.General characteristics. 2. Response to ionising radiation", published in International Journal of Radiation Biology, vol. 81 (2005) by kind permission of Taylor & Francis (http://www. tandf.co.uk) ADDRESS OF THE EDITORIAL OFFICE Institute of Nuclear Chemistry and Technology Dorodna 16, 03-195 Warszawa, POLAND phone: (+4822) 811 06 56, fax: (+4822) 81115 32, e-mail: [email protected] Papers are published in the form as received from the Authors The L5178Y sublines: a summary of 40 year studies in Warsaw The purpose of this report has been to review and summarise the results of 40 year studies concerning the general characteristics and response to UVC radiation, hydrogen peroxide and ionising radiation of the pair of L5178Y (LY) sublines, LY-R and LY-S, that differ in sen- sitivity to various DNA damaging agents. Comparison of karyotypes shows a number of differences in the banding patterns. Differences are found in ion transport and the ganglioside pattern of the plasma membranes, as well as in the content and turnover rate of poly(ADP-ribose) polymers. Nuclear matrix proteins show a differential affinity to these polymers. A unique property of the pair of LY sublines is inverse cross-sensitivity to X-rays and hydrogen peroxide, with cross-sensitivities to hydrogen peroxide and UVC, as well as to UVC and a platinum complex (cwplatin analogue). Initial DNA damage and repair and various aspects of the cellular response were determined in cells damaged with these agents. The higher sensitivity of LY-R cells to hydrogen peroxide, as compared to LY-S cells, is causally related to the higher content of iron ions in these cells and less efficient antioxidant defence system. Sensitivity of LY-R cells to UVC radiation and platinum complexes is explained by impaired excision repair (the incision step is missing). The reviewed data on the response of LY sublines to ionising radiation point to the key importance of DNA damage repair and fixation for the ultimate fate of the irradiated LY cell. The cause of slow double strand break (DSB) repair in LY-S cells is not identified but the defect (in non-homologous end-joining - NHEJ) explains most features of the cellular response to irradiation, as compared to the repair-competent LY-R cells. The most prominent are: very high radiosensitivity of Gl cells, extensive poly(ADP-ribose) dependent damage fixation, long G2 arrest, considerable chromosomal damage seen as premature chro- matin condensation (PCC) fragments and aberrations in metaphase cells. The main cause of radiosensitivity difference between LY sublines lays in DNA repair/damage fixation ability. At the level of damage corresponding to a comparable lethal effect, the type of death differs between LY sublines; LY-S cells die by apoptosis, whereas LY-R cells - by necrosis. This ob- servation is consistent with differential expression of proteins that are pro- or anti-apoptotic. The prominent role of poly(ADP-ribosylation) in the response of LY-S cells apparently is connected with damage fixation, but is in contrast with other hypersensitive to X/y-radiation cell lines with DSB repair defects. Comparison of LY sublines also indicates that their anti- oxidant defence system is of considerable importance in their susceptibility to hydrogen per- oxide, but much less so in radiosensitivity. Podlinie L5178Y: podsumowanie 40 lat badań w Warszawie Celem raportu jest przegląd i podsumowanie wyników 40 lat badań pary podlinii L5178Y (LY), LY-R i LY-S, różniących się wrażliwością na różne czynniki uszkadzające DNA. Bada- nia te dotyczyły ogólnej charakterystyki oraz odpowiedzi na nadtlenek wodoru, promieniowa- nie UVC i promieniowanie jonizujące. Porównanie kariotypów wykazało szereg różnic w układzie prążków. Znaleziono róż- nice w transporcie jonów, składzie gangliozydów błon plazmatycznych, zawartości i obrocie polimerów poli(ADP-rybozy). Białka zrębu jądrowego wykazują zróżnicowane powinowactwo do tych polimerów. Unikatową właściwością pary podlinii LY jest odwrotna krzyżowa wraż- liwość na promieniowanie X i nadtlenek wodoru z jednoczesną krzyżową wrażliwością na nadtlenek wodoru i promieniowanie UVC, a także na promieniowanie UVC i kompleks platyny (analog c/jplatyny). W komórkach uszkadzanych tymi czynnikami charakteryzowano uszkodzenia początkowe DNA, ich naprawę oraz różne aspekty odpowiedzi komórkowej. Wyższa wrażliwość na nadtlenek wodoru komórek LY-R w porównaniu z LY-S spowodowana jest wyższą zawartością jonów żelaza w komórkach tej podlinii i mniej skutecznym układem obrony antyoksydacyjnej. Wrażliwość komórek LY-R na promieniowanie UVC i kompleksy platyny wyjaśniono, charakteryzując defekt w naprawie z wycięciem (brak nacięcia nici DNA). Omówione w raporcie dane na temat odpowiedzi podlinii LY na promieniowanie joni- zujące wskazują na kluczową rolę naprawy i utrwalania uszkodzeń DNA dla dalszych losów napromienionych komórek LY. Przyczyna powolnego łączenia pęknięć podwójnoniciowych DNA w komórkach LY-S nie została do końca zidentyfikowana. Obserwowany defekt w ukła- dzie niehomologicznego łączenia pęknięć wyjaśnia jednak większość różnic w odpowiedzi na promieniowanie w porównaniu z komórkami LY-R, posiadającymi sprawny układ naprawy. Najważniejsze cechy odpowiedzi komórek LY-S są to: bardzo wysoka promieniowrażliwość w fazie Gl, bardzo znaczne utrwalanie uszkodzeń zależne od poli(ADP-rybozylacji), długie opóźnienie mitotyczne, liczne uszkodzenia chromosomów widoczne jako fragmenty PCC (metoda przedwczesnej kondensacji chromatyny) i aberracje w komórkach metafazalnych. Główną przyczyną różnicy w promieniowrażliwości podlinii LY jest relacja między zdolnością naprawy i zakresem utrwalania. Przy poziomie uszkodzeń dającym porównywalny skutek letalny, typ śmierci komórkowej różni się w podliniach: komórki LY-S umierają śmier- cią apoptotyczną, zaś LY-R - śmiercią nekrotyczną. Obserwacja ta odpowiada zróżnicowanej ekspresji białek pro- lub anty-apoptotycznych w obu podliniach. Znacząca rola poli(ADP-ry- bozylacji) w odpowiedzi komórek LY-S na promieniowanie najprawdopodobniej związana jest z utrwalaniem uszkodzeń; cechy tej jednak nie wykazują inne nadwrażliwe na promie- niowanie X/y linie komórkowe z defektem naprawy pęknięć podwójnoniciowych. Z porówna- nia podlinii LY wynika też, że sprawność ich systemu obrony antyoksydacyjnej jest bardzo ważna we wrażliwości na nadtlenek wodoru, znacznie mniej natomiast - w promieniowrażli- wości. CONTENTS 1. INTRODUCTION 7 2. GENERAL CHARACTERISTICS 8 2.1. Cell cycle 8 2.2. Karyotype 8 2.3. Telomeres 9 2.4. DNA domains 9 2.5. Plasma membranes 9 2.5./ Lipid composition 10 2.5.2. /OH content and transport 10 2.5.3. Other transport systems 11 2.5.4. Osmotic fragility 12 2.5.5. Membrane potential 12 2.6. Arachidonic acid metabolism 12 2.7. Sensitivity profiles 12 2.8. PoIy(ADP-ribosylation) 13 3. RESPONSE TO HYDROGEN PEROXIDE 16 3.1. DNA damage related to iron content 16 3.2. Antioxidant defence system and NF-KB translocation 17 4. RESPONSE TO UVC RADIATION 19 4.1. Survival and DNA repair 20 4.2. Mutagenesis 21 4.3. Effects of combined UVC and benzamide or caffeine treatment 21 4.4. UVC-induced alterations in chromatin organisation 22 5. CELLULAR RESPONSE TO IONISING RADIATION 23 5.1. Cell cycle: progression and radiosensitivity fluctuations 24 5.2. Post-irradiation poly(ADP-ribosylation) 26 5.3. Post-irradiation metabolism of arachidonic acid 27 5.4. Stimulation of tyrosine kinase activity 28 5.5. Apoptosis 30 5.6. DNA damage induction and repair 32 5.7. Mutagenesis 34 5.8. NHEJ defect in LY-S cells 34 5.9. DNA damage fixation 36 6. CONCLUDING REMARKS 38 7. REFERENCES 39 1. INTRODUCTION The original L5178Y cells were obtained from a methylcholantrene-induced lymphoma in DBA2 mouse on 8 July 1951 by Law at the Yale University; this fact is noted in the line's "family name": L for lymphoma, followed by the date of isolation and Y for Yale. This seemed somewhat lengthy and about 20 years ago was shortened to LY. The original acronym, however, is always given at the beginning of each paper. The L5178Y-S (LY-S) subline is the first mammalian radiation sensitive cell line to be reported. It was isolated from the parental L5178Y line (later called LY-R) and characterised by Alexander and Mikulski [1]. In 1983 the general characteristics of both LY sublines and their relation to other L5178Y lines was published [2] together with a description of sponta- neous conversion of LY-R phenotype into that of LY-S under in vitro conditions. Activation and silencing of numerous gene groups are more plausible as a mechanism of this conversion than a single mutation in a pleiotropic gene, since the comparison of karyotypes ([3], O. Ro- siek, unpublished, A. Wójcik, unpublished) shows a number of translocations and differences in the banding patterns of LY-R vs LY-S. Both sublines carry a heterozygous inactivating mutation in Tp53 [4, 5]. References are omitted to other, better known members of the L5178Y family, such as the LY 3.7.2C Tk+/- line applied in mutagenesis tests, the radiosensitive Japanese M10 mutant, the L5178Y-S/S cells grown by J.T. Lett in simplified culture medium and exhibiting the lowest mean lethal dose among mammalian cells, and the radioresistant variants obtained by V.D. Courtenay in the United Kingdom and H.H. Evans in the USA. In the passing years many new radiosensitive mutants of mammalian cells were obtain- ed and characterised (reviewed in [6]); they have been widely used in research and have expanded our knowledge of DNA repair mechanisms that act in mammalian cells damaged by ionising radiation.
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