OB-Folds and Genome Maintenance: Targeting Protein-DNA Interactions for Cancer Therapy.
OB-Folds and Genome Maintenance: Targeting Protein-DNA Interactions for Cancer Therapy.
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DOI：
10.3390/cancers13133346
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发表时间：
2021-07-03
期刊：
影响因子：
5.2
通讯作者：
Turchi JJ
中科院分区：
文献类型：
--
作者：
Par S;Vaides S;VanderVere-Carozza PS;Pawelczak KS;Stewart J;Turchi JJ
基因组复制、修复、重组和DNA损伤反应（DDR）依赖于一系列DNA结合蛋白来执行和调节这些关键途径。有许多支持DNA结合的结构基序，其中包括寡核苷酸/寡糖结合折叠（OB-折叠）。OB-folds在生命树中被发现，在染色体的维持和稳定性中起着关键作用。本文综述了OB-折叠蛋白在DNA损伤反应、复制和修复中的结构、功能和参与情况。我们强调了一组OB-折叠DNA结合蛋白，并讨论了如何破坏这些关键的蛋白质-DNA相互作用，可以利用在癌症治疗。基因组稳定性和维持途径沿着其必需的蛋白质对于遗传物质的精确复制、突变避免和包括癌症在内的人类疾病的抑制至关重要。这些蛋白质中的许多通过直接结合DNA参与这些途径，并且一个子集采用寡核苷酸/寡糖结合折叠（OB-折叠）来促进蛋白质-DNA相互作用。OB-折叠基序允许与单链DNA（ssDNA）的序列独立结合，并且可以用于将特定蛋白质定位在特定DNA结构处，然后通过蛋白质-蛋白质相互作用基序组装机器以催化DNA的复制、修复或重组。本文综述了OB-折叠的结构组织的一些最相关的OB-折叠蛋白质的肿瘤学和药物发现。我们讨论了它们在DNA代谢中的各自作用，对这些基序进行药物化的进展以及它们作为潜在癌症治疗剂的效用。虽然蛋白质-DNA相互作用最初被认为是不可治愈的，但最近关于靶向含有OB折叠的蛋白质的分子的成功报道表明并非如此。开发靶向OB-folds的药物的潜力尚处于起步阶段，但如果成功，将扩大影响基因组稳定性和维持途径的机会，以实现更有效的癌症治疗。
Genome replication, repair, recombination, and the DNA damage response (DDR) rely on a cadre of DNA binding proteins to execute and regulate these critical pathways. There are many structural motifs that support DNA-binding and included in these is the oligonucleotide/oligosaccharide binding fold (OB-fold). OB-folds are found across the tree of life and play critical roles in chromosome maintenance and stability. This paper reviews the current state of knowledge regarding structure, function, and involvement of OB-fold proteins in the DNA damage response, replication, and repair. We highlight a group of OB-fold DNA binding proteins and discuss how disruption of these critical protein–DNA interactions can be exploited in cancer therapy. Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a subset employ oligonucleotide/oligosaccharide binding folds (OB-fold) to facilitate the protein–DNA interactions. OB-fold motifs allow for sequence independent binding to single-stranded DNA (ssDNA) and can serve to position specific proteins at specific DNA structures and then, via protein–protein interaction motifs, assemble the machinery to catalyze the replication, repair, or recombination of DNA. This review provides an overview of the OB-fold structural organization of some of the most relevant OB-fold containing proteins for oncology and drug discovery. We discuss their individual roles in DNA metabolism, progress toward drugging these motifs and their utility as potential cancer therapeutics. While protein–DNA interactions were initially thought to be undruggable, recent reports of success with molecules targeting OB-fold containing proteins suggest otherwise. The potential for the development of agents targeting OB-folds is in its infancy, but if successful, would expand the opportunities to impinge on genome stability and maintenance pathways for more effective cancer treatment.
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