The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase, AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2-ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2-ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2-ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase, Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.

中文翻译：

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DNA修复因子ASCC2和ASCC3的相互作用受体细胞癌突变影响

激活信号共整合子复合体的ASCC3亚基是双盒Ski2样核酸解旋酶，可提供单链DNA来通过α-酮戊二酸依赖性双加氧酶AlkBH3进行烷基化损伤修复。其他ASCC组件将ASCC3 / AlkBH3整合到复杂的DNA修复途径中。我们绘制并结构分析了相互作用的ASCC2和ASCC3区域。ASCC3片段包括一个中央螺旋结构域和末端，延伸的臂，这些臂扣紧了紧凑的ASCC2单元。ASCC2-ASCC3接口在进化上是高度保守的，并且包含大量受体癌突变影响的残基。我们量化蛋白质区域对ASCC2-ASCC3相互作用的贡献，观察到癌症中发现的变化导致ASCC2-ASCC3亲和力降低。ASCC3的功能解剖揭示了与剪接体RNA解旋酶Brr2类似的组织和调控。我们的研究结果描述了重要的DNA修复复合物中的功能区，并提出了可能的分子疾病原理。