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Keiichi Takata
유전체 항상성 연구단
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CNDAC-induced DNA double strand breaks cause aberrant mitosis prior to cell death

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Title
CNDAC-induced DNA double strand breaks cause aberrant mitosis prior to cell death
Author(s)
Xiaojun Liu; Yingjun Jiang; Kei-ichi Takata; Billie Nowak; Chaomei Liu; Richard D. Wood; Walter N. Hittelman; William Plunkett
Publication Date
2019-12
Journal
MOLECULAR CANCER THERAPEUTICS, v.18, no.12, pp.2283 - 2295
Publisher
AMER ASSOC CANCER RESEARCH
Abstract
Incorporation of the clinically active deoxycytidine analog, 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosyl-cytosine (CNDAC) into DNA generates single strand breaks that are subsequently converted to double strand breaks (DSBs). Here, we investigated the cellular manifestations of these breaks that link these mechanisms to cell death, and we further tested the relevance of DNA repair pathways in protection of cells against CNDAC damage. The present investigations demonstrate that following exposure to CNDAC and a wash into drug-free medium, chromosomal aberrations, DNA strand breaks and multinucleate cells arose. These portended loss of viability and were dependent upon exposure time, CNDAC concentration and passage through mitosis. Following a pulse incubation with CNDAC, live cell imaging using GFP-tagged histone H2B as a marker demonstrated a normal rate of progression to mitosis, but a concentration-dependent delay in passage to a second mitosis. Progression through mitosis was also delayed and accompanied by formation of multinucleate cells. CNDAC-treated cells lacking XPF-ERCC1 nuclease function showed a 16-fold increase in chromosome aberrations. Chromosomal damage in Rad51D mutant cells (homologous recombination repair deficient) were even more severely affected with extensive aberrations. Rodent or human Polq (POLQ) mutant cells, defective in Pol θ-mediated alternative end joining, did not show enhanced cellular sensitivity to CNDAC. These findings are consistent with formation of DSBs in the second S-phase following exposure, resulting in chromosome aberrations, aberrant mitoses, and subsequent apoptosis. C.2019 American Association for Cancer Research.
URI
https://pr.ibs.re.kr/handle/8788114/6702
ISSN
1535-7163
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
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