Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portend poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the proinflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. In this study, we manipulated three putative nuclear localization (NLS1 to -3) and two potential nuclear export signals (NES1 and -2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, MSH3 with this deletion (Δ27bp MSH3) localizes to the cytoplasm, suggesting that NLS1 function in Δ27bp MSH3 is compromised. Overall, MSH3's shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammation-associated neoplastic processes.

中文翻译：

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人类DNA错配修复蛋白MSH3包含核定位和输出信号，这些信号能够响应发炎而使核细胞的穿梭运动。

DNA错配修复的失活推动了结直肠癌（CRC）的肿瘤发生。在选定的四核苷酸重复序列（EMAST）上表现出微卫星变化升高的CRCs表现出核MutS同源物3（MSH3）表达降低，周围有炎症，预示患者预后不良。响应促炎性细胞因子白介素6（IL-6），MSH3可逆地从细胞核移至胞质溶胶，表明MSH3可能是一种穿梭蛋白。在这项研究中，我们操纵了MSH3中的三个假定核定位（NLS1至-3）和两个潜在核输出信号（NES1和-2）。我们发现NLS1和NLS2都具有核导入功能，而NLS1负责全长MSH3中的核定位。我们还发现NES1和NES2协同工作以最大化核出口，两者都是IL-6诱导的MSH3出口所必需的。我们检查了多态性外显子1内27 bp的缺失（Δ27bp），该缺失在人类CRC细胞和邻居NLS1中频繁发生。在氧化应激下，具有此缺失的MSH3（Δ27bpMSH3）定位在细胞质中，表明NLS1在Δ27bpMSH3中的功能受到损害。总的来说，MSH3对炎症的反应使细胞质中积累。减少的核MSH3会增加EMAST和DNA损伤。我们建议与NLS1相邻的多态性序列可能会增强细胞溶质的保留，这对与炎症相关的肿瘤形成过程具有临床意义。具有此缺失的MSH3（Δ27bpMSH3）定位于细胞质，表明Δ27bpMSH3中的NLS1功能受到损害。总的来说，MSH3对炎症的反应使细胞质中积累。减少的核MSH3会增加EMAST和DNA损伤。我们建议与NLS1相邻的多态性序列可能会增强胞质保留，这对与炎症相关的肿瘤形成过程具有临床意义。具有此缺失的MSH3（Δ27bpMSH3）定位于细胞质，表明Δ27bpMSH3中的NLS1功能受到损害。总的来说，MSH3对炎症的反应使细胞质中积累。减少的核MSH3会增加EMAST和DNA损伤。我们建议与NLS1相邻的多态性序列可能会增强胞质保留，这对与炎症相关的肿瘤形成过程具有临床意义。