Abstract:
:The role of the mismatch repair (MMR) system in correcting base-base mismatches is well established; its involvement in the response to DNA double strand breaks, however, is less clear. We investigated the influence of the essential component of MMR, the hMLH1 protein, on the cellular response to DNA-double strand breaks induced by treatment with SN-38, the active metabolite of topoisomerase I inhibitor irinotecan, in a strictly isogenic cell system (p53(wt), hMLH1(+)/p53(wt), hMLH1(-)). By using hMLH1 expressing clones or cells transduced with the hMLH1-expressing adenovirus as well as siRNA technology, we show that in response to SN-38-induced DNA damage the MMR proficient (MMR(+)) cells make: (i) a stronger G2/M arrest, (ii) a subsequent longer tetraploid G1 arrest, (iii) a stronger activation of Chk1 and Chk2 kinases than the MMR deficient (MMR(-)) counterparts. Both Cdk2 and Cdk4 kinases contribute to the basal tetraploid G1 arrest in MMR(+) and MMR(-) cells. Although the Chk1 kinase is involved in the G2/M arrest, neither Chk1 nor Chk2 are involved in the enhancement of the tetraploid G1 arrest. The long-lasting tetraploid G1 arrest of MMR(+) cells is associated with their lower clonogenic survival after SN-38 treatment, the abrogation of the tetraploid G1 arrest resulted in their better clonogenic survival. These data show that the stabilization of the tetraploid G1 arrest in response to double strand breaks is a novel function of the MMR system that contributes to the lesser survival of MMR(+) cells.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Bhonde MR,Hanski ML,Stehr J,Jebautzke B,Peiró-Jordán R,Fechner H,Yokoyama KK,Lin WC,Zeitz M,Hanski Cdoi
10.1002/ijc.24893subject
Has Abstractpub_date
2010-06-15 00:00:00pages
2813-25issue
12eissn
0020-7136issn
1097-0215journal_volume
126pub_type
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