Kitano Taisuke, Zhu Zida, Minami Naoya, Orino Koichi, Yoshikawa Yasunaga
Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
Front Vet Sci. 2025 Jul 10;12:1570720. doi: 10.3389/fvets.2025.1570720. eCollection 2025.
Elephants exhibit remarkable resistance to cancer, and understanding these mechanisms has focused on their potential applications in cancer prevention and treatment in humans. A genome-wide comparative analysis identified that the accelerated regions in elephants are enriched in Fanconi anemia (FA) complementation group L (FANCL), a ubiquitin E3 ligase that mediates the monoubiquitylation of FANCD2 as an essential step in the FA pathway. The FA pathway plays a crucial role in DNA interstrand crosslink (ICL) repair, contributing substantially to genome stability and cancer resistance. In this study, we investigated the differences in ICL repair via the FA pathway, including the function of FANCL, as well as the DNA damage response to ICLs between elephants and humans. We found that elephant fibroblasts exhibited higher sensitivity to ICL-inducing treatments, such as mitomycin C and trimethylpsoralen plus UVA (PUVA), than human fibroblasts, while showing comparable or reduced sensitivity to other DNA-damaging agents, such as doxorubicin and bleomycin. Functional analyses revealed that elephant and human FANCL performed similarly in mediating FANCD2 monoubiquitylation and cell viability following mitomycin C treatment. Interestingly, elephant fibroblasts exhibited a more potent and prolonged activation of p21 and sustained DNA repair responses, such as FANCD2 monoubiquitylation and increased RAD51expression, following ICL-induced treatments. Moreover, elephant fibroblasts showed significantly greater RAD51 foci formation than human fibroblasts after PUVA treatment, even under comparable levels of DNA damage. These findings suggest that elephants efficiently repair ICLs in growth-arrested cells likely through robust p21 activation. This study provides new insights into the cancer resistance mechanisms of elephants and offers novel approaches for cancer prevention and therapy.
大象对癌症表现出显著的抵抗力，而对这些机制的理解集中在它们在人类癌症预防和治疗中的潜在应用上。全基因组比较分析发现，大象的加速区域富含范可尼贫血（FA）互补组L（FANCL），这是一种泛素E3连接酶，介导FANCD2的单泛素化，是FA途径中的关键步骤。FA途径在DNA链间交联（ICL）修复中起关键作用，对基因组稳定性和抗癌能力有重要贡献。在本研究中，我们调查了通过FA途径进行ICL修复的差异，包括FANCL的功能，以及大象和人类对ICL的DNA损伤反应。我们发现，大象成纤维细胞对丝裂霉素C和三甲基补骨脂素加紫外线A（PUVA）等ICL诱导处理比人类成纤维细胞更敏感，而对阿霉素和博来霉素等其他DNA损伤剂的敏感性相当或降低。功能分析表明，大象和人类的FANCL在介导丝裂霉素C处理后的FANCD2单泛素化和细胞活力方面表现相似。有趣的是，在ICL诱导处理后，大象成纤维细胞表现出更强、更持久的p21激活和持续的DNA修复反应，如FANCD2单泛素化和RAD51表达增加。此外，即使在DNA损伤水平相当的情况下，PUVA处理后大象成纤维细胞的RAD51焦点形成也比人类成纤维细胞显著更多。这些发现表明，大象可能通过强大的p21激活有效地修复生长停滞细胞中的ICL。这项研究为大象的抗癌机制提供了新的见解，并为癌症预防和治疗提供了新的方法。
