PALB2 (partner and localizer of BRCA2).
PALB2 (partner and localizer of BRCA2).
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DOI：
10.4267/2042/69016
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发表时间：
2018-04-01
影响因子：
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通讯作者：
Andreassen, Paul R
中科院分区：
文献类型：
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作者：
Hanenberg, Helmut;Andreassen, Paul R
PALB 2（Partner and Localizer of BRCA 2）是一种与BRCA 2相互作用的蛋白质。随后，PALB 2被认为是通过同源重组（HR）进行DNA修复的细胞机制中的齿轮。PALB 2还介导S和G2 DNA损伤检查点，并且在保护转录活性基因免受遗传毒性应激中具有明显的功能。PALB2也与BRCA1相互作用，由BRCA1定位，并在BRCA1下游发挥作用。此外，PALB2与HR的其他重要效应物相互作用，包括RAD51和RAD51C以及BRCA2。与其在HR中的功能及其与关键HR蛋白的相互作用一致，PALB 2缺陷细胞对电离辐射和DNA链间交联剂（如丝裂霉素C和顺铂）高度敏感。从机制上讲，PALB 2是HR所必需的，它介导BRCA 2和RAD 51重组酶募集到DNA损伤位点。与BRCA1、BRCA2、RAD51和RAD51C的双等位基因功能丧失突变相似，PALB 2中的双等位基因突变导致范可尼贫血（FA），这是一种罕见的儿童疾病，与进行性骨髓衰竭、先天性异常以及白血病和实体瘤的易感性相关。由于其密切的功能关系，PALB 2和BRCA 2的双等位基因突变导致特别严重的FA形式，称为FANCN和FANCD 1，两者均以严重的先天性异常和各种癌症的极早期发作为特征。这包括急性白血病、肾母细胞瘤、髓母细胞瘤和神经母细胞瘤。此外，PALB2的杂合子生殖系突变，如上文列出的其他几个必需HR基因的突变，会增加乳腺癌和胰腺癌的易感性。
PALB2 (Partner and Localizer of BRCA2) was first identified as a BRCA2-interacting protein. Subsequently, PALB2 has been recognized as a cog in the cellular machinery for DNA repair by homologous recombination (HR). PALB2 also mediates S and G2 DNA damage checkpoints, and has an apparent function in protecting transcriptionally active genes from genotoxic stress. PALB2 also interacts with, is localized by, and functions downstream of BRCA1. Further, PALB2 interacts with other essential effectors of HR, including RAD51 and RAD51C, as well as BRCA2. Consistent with its function in HR and its interaction with key HR proteins, PALB2-deficient cells are hypersensitive to ionizing radiation and DNA interstrand crosslinking agents such as mitomycin C and cisplatin. Mechanistically, PALB2 is required for HR by mediating the recruitment of BRCA2 and the RAD51 recombinase to sites of DNA damage. Similar to bi-allelic loss-of-function mutations of BRCA1, BRCA2, RAD51 and RAD51C, bi-allelic mutations in PALB2 cause Fanconi anemia (FA), a rare childhood disorder which is associated with progressive bone marrow failure, congenital anomalies, and a predisposition to leukemia and solid tumors. Due to their close functional relationship, bi-allelic mutations of PALB2 and BRCA2 cause particularly severe forms of FA, called FANCN and FANCD1, both characterized by severe congenital abnormalities and very early onset of various cancers. This includes acute leukemias, Wilms tumor, medulloblastoma and neuroblastomas. Also, heterozygous germ-line mutations of PALB2, like mutations in several other essential HR genes listed above, yield an increased susceptibility to breast and pancreatic cancer.