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Noncoding mutation hotspots have been identified in melanoma and many of them occur at the binding sites of E26 transformation-specific (ETS) proteins; however, their formation mechanism and functional impacts are not fully understood. Here, we used UV (Ultraviolet) damage sequencing data and analyzed cyclobutane pyrimidine dimer (CPD) formation, DNA repair, and CPD deamination in human cells at single-nucleotide resolution. Our data show prominent CPD hotspots immediately after UV irradiation at ETS binding sites, particularly at sites with a conserved TTCCGG motif, which correlate with mutation hotspots identified in cutaneous melanoma. Additionally, CPDs are repaired slower at ETS binding sites than in flanking DNA. Cytosine deamination in CPDs to uracil is suggested as an important step for UV mutagenesis. However, we found that CPD deamination is significantly suppressed at ETS binding sites, particularly for the CPD hotspot on the 5′ side of the ETS motif, arguing against a role for CPD deamination in promoting ETS-associated UV mutations. Finally, we analyzed a subset of frequently mutated promoters, including the ribosomal protein genesRPL13AandRPS20, and found that mutations in the ETS motif can significantly reduce the promoter activity. Thus, our data identify high UV damage and low repair, but not CPD deamination, as the main mechanism for ETS-associated mutations in melanoma and uncover important roles of often-overlooked mutation hotspots in perturbing gene transcription. 

A strategy for developing irregular materials can lead to a wide range of functional properties. 

Mechanical cloaks are materials engineered to manipulate the elastic response around objects to make them indistinguishable from their homogeneous surroundings. Typically, methods based on material-parameter transformations are used to design optical, thermal, and electric cloaks. However, they are not applicable in designing mechanical cloaks, since continuum-mechanics equations are not form invariant under general coordinate transformations. As a result, existing design methods for mechanical cloaks have so far been limited to a narrow selection of voids with simple shapes. To address this challenge, we present a systematic, data-driven design approach to create mechanical cloaks composed of aperiodic metamaterials using a large precomputed unit cell database. Our method is flexible to allow the design of cloaks with various boundary conditions, multiple loadings, different shapes and numbers of voids, and different homogeneous surroundings. It enables a concurrent optimization of both topology and properties distribution of the cloak. Compared to conventional fixed-shape solutions, this results in an overall better cloaking performance and offers unparalleled versatility. Experimental measurements on additively manufactured structures further confirm the validity of the proposed approach. Our research illustrates the benefits of data-driven approaches in quickly responding to new design scenarios and resolving the computational challenge associated with multiscale designs of functional structures. It could be generalized to accommodate other applications that require heterogeneous property distribution, such as soft robots and implants design.