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Title

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

AuthorsPincheira, Juana; De la Torre, Consuelo; Rodríguez, Natalie; Valenzuela, Carlos Y.
KeywordsDNA damage and repair
G2-prophase checkpoint adaptation
Premitotic DSBs and chromosomal aberrations
Anti-tumoral genotoxic drugs
Issue Date29-Jun-2012
PublisherSociedad de Biología de Chile
CitationBiol Res 45: 177-182, 2012
AbstractWe analyzed the in vitro eff ects 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 caff eine-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.
Description6 p.-1 tab.
Publisher version (URL)http://dx.doi.org/10.4067/S0716-97602012000200010
URIhttp://hdl.handle.net/10261/108837
DOI10.4067/S0716-97602012000200010
ISSN0716-9760
E-ISSN0717-6287
Appears in Collections:(CIB) Artículos
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