DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway.
DNA damage response and cancer therapeutics through the lens of the Fanconi Anemia DNA repair pathway.
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DOI：
10.1186/s12964-017-0195-9
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发表时间：
2017-10-10
期刊：
影响因子：
--
通讯作者：
Nandi S
中科院分区：
文献类型：
--
作者：
Bhattacharjee S;Nandi S
范可尼贫血（FA）是一种罕见的遗传性基因组不稳定性疾病，由参与DNA链间交联（ICL）修复的基因突变引起。FA信号传导网络包含独特的核蛋白复合物，其介导FANCD 2和FANCI异二聚体的单泛素化，并协调下游DNA修复途径的活性，包括核苷酸切除修复、跨损伤合成和同源重组。FA蛋白在ICL修复的不同步骤中起作用，参与DNA损伤的感知、识别和加工。多蛋白网络受到复杂机制的严格调控，如泛素化、磷酸化和降解信号，这些信号对维持基因组完整性和抑制肿瘤发生至关重要。在这里，我们讨论了最近的进展，我们的理解如何FA蛋白参与ICL修复和调节FA信号网络，确保基因组的安全。我们进一步讨论了设计抑制FA通路的小分子抑制剂的潜在应用，并且与可用于癌症治疗的DNA修复酶一起合成致死。
Fanconi Anemia (FA) is a rare, inherited genomic instability disorder, caused by mutations in genes involved in the repair of interstrand DNA crosslinks (ICLs). The FA signaling network contains a unique nuclear protein complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and coordinates activities of the downstream DNA repair pathway including nucleotide excision repair, translesion synthesis, and homologous recombination. FA proteins act at different steps of ICL repair in sensing, recognition and processing of DNA lesions. The multi-protein network is tightly regulated by complex mechanisms, such as ubiquitination, phosphorylation, and degradation signals that are critical for the maintenance of genome integrity and suppressing tumorigenesis. Here, we discuss recent advances in our understanding of how the FA proteins participate in ICL repair and regulation of the FA signaling network that assures the safeguard of the genome. We further discuss the potential application of designing small molecule inhibitors that inhibit the FA pathway and are synthetic lethal with DNA repair enzymes that can be used for cancer therapeutics.
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