PALB2: the hub of a network of tumor suppressors involved in DNA damage responses.
PALB2: the hub of a network of tumor suppressors involved in DNA damage responses.
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DOI：
10.1016/j.bbcan.2014.06.003
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发表时间：
2014-08
影响因子：
11.2
通讯作者：
Andreassen, Paul R.
中科院分区：
文献类型：
--
作者：
Park, Jung-Young;Zhang, Fan;Andreassen, Paul R.
PALB2首先被确定为BRCA2的伙伴，介导其招募到DNA损伤位点。PALB2随后被发现是一个肿瘤抑制基因。该基因的遗传杂合性与乳腺癌和其他部位癌症的风险增加有关。此外，PALB2的双等位基因突变与范可尼贫血有关，范可尼贫血也会增加患恶性疾病的风险。最近的工作已经确定了PALB2的许多相互作用，表明它在肿瘤抑制因子编码的蛋白质网络中起作用。值得注意的是，许多这些肿瘤抑制因子与细胞对DNA损伤的反应有关。PALB2在该网络头部的DNA双链断裂上的招募是通过泛素依赖的信号通路进行的，该通路涉及RAP80、Abraxas和BRCA1肿瘤抑制因子。接下来，PALB2与肿瘤抑制因子BRCA2和RAD51重组酶相互作用。这些相互作用通过同源重组（HR）促进DNA修复。最近，PALB2已被发现与RAD51平行体、RAD51C以及翻译聚合酶pol η结合，这两种酶都是在HR中起作用的肿瘤抑制因子。此外，与MRG15的相互作用与染色质调控有关，可能促进受损染色质中的DNA修复。最后，PALB2与KEAP1相互作用，KEAP1是氧化应激反应的调节因子。PALB2网络似乎介导了基因组稳定性的维持，可能解释了许多具有相似肿瘤谱的相应基因的关联，并可能提供新的治疗机会。
PALB2 was first identified as a partner of BRCA2 that mediates its recruitment to sites of DNA damage. PALB2 was subsequently found as a tumor suppressor gene. Inherited heterozygosity for this gene is associated with an increased risk of cancer of the breast and other sites. Additionally, biallelic mutation of PALB2 is linked to Fanconi anemia, which also has an increased risk of developing malignant disease. Recent work has identified numerous interactions of PALB2, suggesting that it functions in a network of proteins encoded by tumor suppressors. Notably, many of these tumor suppressors are related to the cellular response to DNA damage. The recruitment of PALB2 to DNA double-strand breaks at the head of this network is via a ubiquitin-dependent signaling pathway that involves the RAP80, Abraxas and BRCA1 tumor suppressors. Next, PALB2 interacts with BRCA2, which is a tumor suppressor, and with the RAD51 recombinase. These interactions promote DNA repair by homologous recombination (HR). More recently, PALB2 has been found to bind the RAD51 paralog, RAD51C, as well as the translesion polymerase pol η, both of which are tumor suppressors with functions in HR. Further, an interaction with MRG15, which is related to chromatin regulation, may facilitate DNA repair in damaged chromatin. Finally, PALB2 interacts with KEAP1, a regulator of the response to oxidative stress. The PALB2 network appears to mediate the maintenance of genome stability, may explain the association of many of the corresponding genes with similar spectra of tumors, and could present novel therapeutic opportunities.
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影响因子：
9.8
作者：
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