视网膜母细胞瘤抑癌蛋白（RB）与多种表观遗传修饰酶发生物理和功能性相互作用，以控制转录调节、应对复制压力、促进DNA损伤应答和修复，并调节基因组稳定性。为了更好地了解RB功能障碍如何影响基因组稳定性的表观遗传调控，并确定这些变化是否代表了RB缺失癌细胞可利用的弱点，我们进行了基于成像的筛选，以识别促进DNA损伤并削弱RB缺失细胞存活能力的表观遗传抑制剂。我们发现，单纯RB缺失导致复制依赖性多聚腺苷二磷酸核糖化（PARylation）水平升高，并且通过捕获PARP酶在染色质上从而阻止PARylation使RB缺失细胞在有未解决复制压力的情况下进入有丝分裂。这些缺陷导致DNA损伤水平升高和细胞存活能力下降。我们证明了这种敏感性在针对PARP1和PARP2的一系列药物中是保守的，并且可以通过RB蛋白的再表达来抑制。综上所述，这些数据表明，针对PARP1和PARP2的药物可能在治疗RB缺失癌症中具有临床相关性。（2023年Zamalloa等人）

The retinoblastoma tumor suppressor protein (RB) interacts physically and functionally with a number of epigenetic modifying enzymes to control transcriptional regulation, respond to replication stress, promote DNA damage response and repair, and regulate genome stability. To better understand how disruption of RB function impacts epigenetic regulation of genome stability and determine whether such changes represent exploitable weaknesses of RB-deficient cancer cells, we performed an imaging-based screen to identify epigenetic inhibitors that promote DNA damage and compromise the viability of RB-deficient cells. We found that loss of RB alone leads to high levels of replication-dependent poly-ADP ribosylation (PARylation) and that preventing PARylation by trapping PARP enzymes on chromatin enables RB-deficient cells to progress to mitosis with unresolved replication stress. These defects contribute to high levels of DNA damage and compromised cell viability. We demonstrate this sensitivity is conserved across a panel of drugs that target both PARP1 and PARP2 and can be suppressed by reexpression of the RB protein. Together, these data indicate that drugs that target PARP1 and PARP2 may be clinically relevant for RB-deficient cancers.© 2023 Zamalloa et al.