Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC.
The nucleoside analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosyl-cytosine (CNDAC), currently in clinical trials for hematologic malignancies, has a novel action mechanism of causing a single-strand break after its incorporation into DNA. Double-strand breaks (DSBs) are generated thereafter in vivo and, if not repaired, pose lethal impact on cell survival. This study sought to define the mechanisms by which CNDAC-induced DSBs are formed and repaired. We demonstrated that single-strand breaks induced by CNDAC incorporation into DNA were converted to DSBs when cells progressed into the subsequent S-phase. CNDAC-induced DSBs were products of replication, rather than a consequence of apoptosis. ATM, the activator of homologous recombination (HR), was essential for cell survival after CNDAC treatment in cell lines and in primary acute myeloid leukemia samples, as were the HR components, Rad51, Xrcc3, and Brca2. Furthermore, formation of sister chromatid exchanges, a hallmark of HR, increased significantly after CNDAC-treated cells had progressed into a second replication cycle. In contrast, neither the replication stress sensor ATR nor DNA-PK, the initiator of nonhomologous end-joining of DSB, was involved in repair of CNDAC-induced damage. Together, these results indicate that HR, but not nonhomologous end-joining, is the major repair or survival mechanism for DNA damage caused by CNDAC.
Liu
Xiaojun
X
Department of Experimental Therapeutics, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Wang
Yaqing
Y
Benaissa
Sherri
S
Matsuda
Akira
A
Kantarjian
Hagop
H
Estrov
Zeev
Z
Plunkett
William
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011995:Recombination, Genetic / Q000187:drug effects*; D012854:Sister Chromatid Exchange / Q000187:drug effects; D055815:Young Adult
D004277:DNA, Single-Stranded; D003561:Cytarabine; C070279:2'-cyano-2'-deoxyarabinofuranosylcytosine