Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals

We analyzed the in vitro effects of the anti-tumoral drugs doxorubicin, cytosine arabinoside and hydroxyurea on the G2-prophase checkpoint in lymphocytes from healthy individuals. At biologically equivalent concentrations, the induced DNA damage activated the corresponding checkpoint. Thus: i) there...

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Autores principales:	Pincheira,Juana, de la Torre,Consuelo, Rodríguez,Natalie, Valenzuela,Carlos Y
Lenguaje:	English
Publicado:	Sociedad de Biología de Chile 2012
Materias:	DNA damage and repair G2-prophase checkpoint adaptation premitotic DSBs and chromosomal aberrations anti-tumoral genotoxic drugs
Acceso en línea:	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602012000200010
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spelling	oai:scielo:S0716-976020120002000102012-08-30Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individualsPincheira,Juanade la Torre,ConsueloRodríguez,NatalieValenzuela,Carlos Y DNA damage and repair G2-prophase checkpoint adaptation premitotic DSBs and chromosomal aberrations anti-tumoral genotoxic drugs We analyzed the in vitro effects of the anti-tumoral drugs doxorubicin, cytosine arabinoside and hydroxyurea on the G2-prophase checkpoint in lymphocytes from healthy individuals. At biologically equivalent concentrations, the induced DNA damage activated the corresponding checkpoint. Thus: i) there was a concentration-dependent delay of G2 time and an increase of both the total DNA lesions produced and repaired before metaphase and; ii) G2-checkpoint adaptation took place as chromosome aberrations (CAs) started to appear in the metaphase, indicating the presence of unrepaired double-strand breaks (DSBs) in the previous G2. The checkpoint ATM/ATR kinases are involved in DSB repair, since the recorded frequency of CAs increased when both kinases were caffeine-abrogated. In genotoxic-treated cells about three-fold higher repair activity was observed in relation to the endogenous background level of DNA lesions. The maximum rate of DNA repaired was 3.4 CAs/100 metaphases/hour, this rise being accompanied by a modest 1.3 fold lengthening of late G2 prophase timing. Because of mitotic chromosome condensation, no DSBs repair can take place until the G1 phase of the next cell cycle, when it occurs by DNA non-homologous end joining (NHEJ). Chromosomal rearrangements formed as a consequence of these error-prone DSB repairs ensure the development of genome instability through the DNA-fusion-bridge cycle. Hence, adaptation of the G2 checkpoint supports the appearance of secondary neoplasia in patients pretreated with genotoxic drugs.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.45 n.2 20122012-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602012000200010en10.4067/S0716-97602012000200010
institution	Scielo Chile
collection	Scielo Chile
language	English
topic	DNA damage and repair G2-prophase checkpoint adaptation premitotic DSBs and chromosomal aberrations anti-tumoral genotoxic drugs
spellingShingle	DNA damage and repair G2-prophase checkpoint adaptation premitotic DSBs and chromosomal aberrations anti-tumoral genotoxic drugs Pincheira,Juana de la Torre,Consuelo Rodríguez,Natalie Valenzuela,Carlos Y Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
description	We analyzed the in vitro effects of the anti-tumoral drugs doxorubicin, cytosine arabinoside and hydroxyurea on the G2-prophase checkpoint in lymphocytes from healthy individuals. At biologically equivalent concentrations, the induced DNA damage activated the corresponding checkpoint. Thus: i) there was a concentration-dependent delay of G2 time and an increase of both the total DNA lesions produced and repaired before metaphase and; ii) G2-checkpoint adaptation took place as chromosome aberrations (CAs) started to appear in the metaphase, indicating the presence of unrepaired double-strand breaks (DSBs) in the previous G2. The checkpoint ATM/ATR kinases are involved in DSB repair, since the recorded frequency of CAs increased when both kinases were caffeine-abrogated. In genotoxic-treated cells about three-fold higher repair activity was observed in relation to the endogenous background level of DNA lesions. The maximum rate of DNA repaired was 3.4 CAs/100 metaphases/hour, this rise being accompanied by a modest 1.3 fold lengthening of late G2 prophase timing. Because of mitotic chromosome condensation, no DSBs repair can take place until the G1 phase of the next cell cycle, when it occurs by DNA non-homologous end joining (NHEJ). Chromosomal rearrangements formed as a consequence of these error-prone DSB repairs ensure the development of genome instability through the DNA-fusion-bridge cycle. Hence, adaptation of the G2 checkpoint supports the appearance of secondary neoplasia in patients pretreated with genotoxic drugs.
author	Pincheira,Juana de la Torre,Consuelo Rodríguez,Natalie Valenzuela,Carlos Y
author_facet	Pincheira,Juana de la Torre,Consuelo Rodríguez,Natalie Valenzuela,Carlos Y
author_sort	Pincheira,Juana
title	Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
title_short	Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
title_full	Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
title_fullStr	Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
title_full_unstemmed	Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
title_sort	response of the g2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals
publisher	Sociedad de Biología de Chile
publishDate	2012
url	http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602012000200010
work_keys_str_mv	AT pincheirajuana responseoftheg2prophasecheckpointtogenotoxicdrugsinlymphocytesfromhealthyindividuals AT delatorreconsuelo responseoftheg2prophasecheckpointtogenotoxicdrugsinlymphocytesfromhealthyindividuals AT rodrigueznatalie responseoftheg2prophasecheckpointtogenotoxicdrugsinlymphocytesfromhealthyindividuals AT valenzuelacarlosy responseoftheg2prophasecheckpointtogenotoxicdrugsinlymphocytesfromhealthyindividuals
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Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals

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