RB loss sensitizes cells to replication-associated DNA damage after PARP inhibition by trapping.
RB loss sensitizes cells to replication-associated DNA damage after PARP inhibition by trapping.
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DOI：
10.26508/lsa.202302067
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发表时间：
2023-12
影响因子：
4.4
通讯作者：
Manning, Amity L.
中科院分区：
文献类型：
--
作者：
Zamalloa, Luis Gregory;Pruitt, Margaret M.;Hermance, Nicole M.;Gali, Himabindu;Flynn, Rachel L.;Manning, Amity L.
在通过捕获抑制PARP后，缺乏RB肿瘤抑制因子的细胞经历持续的复制应激和基因组不稳定性，从而损害细胞活力。视网膜母细胞瘤肿瘤抑制蛋白（RB）与许多表观遗传修饰酶在物理和功能上相互作用，以控制转录调控，响应复制应激，促进DNA损伤反应和修复，并调节基因组稳定性。为了更好地了解RB功能的破坏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RB缺陷癌细胞的可利用弱点，我们进行了基于成像的筛选，以确定促进DNA损伤并损害RB缺陷细胞活力的表观遗传抑制剂。我们发现，单独RB的丢失导致高水平的复制依赖性聚ADP核糖基化（PAR化），并且通过在染色质上捕获PARP酶来防止PAR化，使得RB缺陷细胞能够在未解决的复制应激下进行有丝分裂。这些缺陷导致高水平的DNA损伤和细胞活力受损。我们证明了这种敏感性在靶向PARP1和PARP2的一组药物中是保守的，并且可以通过RB蛋白的再表达来抑制。总之，这些数据表明靶向PARP1和PARP2的药物可能与RB缺陷型癌症临床相关。
After PARP inhibition by trapping, cells lacking the RB tumor suppressor experience persistent replication stress and genomic instability that compromise cell viability. 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.
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影响因子：
37.3
作者：
Amato A;Schillaci T;Lentini L;Di Leonardo A
通讯作者：
Di Leonardo A
影响因子：
11.5
作者：
Chen, William S.;Alshalalfa, Mohammed;Feng, Felix Y.
通讯作者：
Feng, Felix Y.
视网膜母细胞瘤抑制组蛋白H3赖氨酸27的蛋白质依赖性甲基化与不可逆的细胞周期出口有关。
影响因子：
7.8
作者：
Blais, Alexandre;van Oevelen, Chris J. C.;Margueron, Raphael;Acosta-Alvear, Diego;Dynlacht, Brian David
通讯作者：
Dynlacht, Brian David
依然氨酸通过蛋白质合成抑制而不是通过靶向冈崎片段来阻止DNA复制。
影响因子：
4.4
作者：
Lukac, David;Machacova, Zuzana;Moudry, Pavel
通讯作者：
Moudry, Pavel
影响因子：
21.3
作者：
Gonzalo, S;García-Cao, M;Blasco, MA
通讯作者：
Blasco, MA