Paviolo Natalia Soledad, Vega María Belén de la, Pansa María Florencia, García Iris Alejandra, Calzetta Nicolás Luis, Soria Gastón, Gottifredi Vanesa
Fundación Instituto Leloir-Instituto de Investigaciones Bioquímicas de Buenos Aires. Buenos Aires, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET. Córdoba, Argentina.
Genet Mol Biol. 2019 Dec 13;43(1 suppl 1):e20190070. doi: 10.1590/1678-4685-GMB-2019-0070. eCollection 2019.
The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombination deficiency of BRCA-mutated cells. Such accumulation of DSBs is inferred mainly from the high levels of DNA damage markers like phosphorylated histone H2AX. Herein, we developed a model of isogenic cell lines to show that depletion of BRCA causes PARPi-triggered cell death, replication stress (phosphorylated-H2AX and 53BP1 foci), and genomic instability. However, persistent DSBs accumulation was not detected under the same experimental conditions. Hence, at least in this cellular model, the trigger for cell death in PARPi-treated BRCA-depleted samples is not the accumulation of unrepaired DSBs. Instead, cell death better correlates with a rapid and aberrant resolution of DSBs by error-prone pathways that leads to severe chromosomic aberrations. Therefore, our results suggest that in PARPi-treated BRCA-deficient cells, chromosome aberrations may dually trigger both genomic instability and cell death.
聚（腺苷二磷酸（ADP）-核糖基）聚合酶抑制剂（PARPi）可选择性杀死具有BRCA1或BRCA2（BRCA）突变的癌细胞。有人提出，PARPi处理后细胞死亡的诱导取决于由于BRCA突变细胞的同源重组缺陷而积累的未修复双链断裂（DSB）。这种DSB的积累主要是从诸如磷酸化组蛋白H2AX等高水平DNA损伤标志物推断出来的。在此，我们建立了一个同基因细胞系模型，以表明BRCA的缺失会导致PARPi触发细胞死亡、复制应激（磷酸化-H2AX和53BP1灶）和基因组不稳定。然而，在相同实验条件下未检测到持续性DSB积累。因此，至少在这个细胞模型中，PARPi处理的BRCA缺失样本中细胞死亡的触发因素不是未修复DSB的积累。相反，细胞死亡与通过易出错途径快速异常修复DSB导致严重染色体畸变的情况更好相关。因此，我们的结果表明，在PARPi处理的BRCA缺陷细胞中，染色体畸变可能双重触发基因组不稳定和细胞死亡。
