Faraco Camila C F, Zhu Wanting, Fortier Anne-Marie, Ramdzan Zubaidah M, Vickridge Elise, Ong Virakbott, Goudreau Félix, Djerir Billel, Bellemare Jérôme, Gu Shujing, Zhang Huanyi, Carroll Brittany L, Krishnan Shreya S, Leduy Lam, Guarné Alba, Park Morag, Maréchal Alexandre, Nepveu Alain
Goodman Cancer Institute, McGill University, Montreal, H3A 1A3, Quebec, Canada.
Department of Biochemistry, McGill University, Montreal, Quebec, H3A 1A1, Canada.
Nucleic Acids Res. 2025 Jul 19;53(14). doi: 10.1093/nar/gkaf706.
The MYC and RAS oncogenes were found early on to cooperate in the transformation of nonimmortalized primary cells, and in tumor development in transgenic mouse models. MYC prevents RAS-induced senescence. Moreover, tumor regression resulting from the suppression of MYC expression is associated with cellular senescence. How MYC prevents RAS-induced senescence and why suppression of MYC in tumors causes senescence remains to be elucidated. Here, we show that MYC interacts with the Pol β DNA polymerase and stimulates its enzymatic activities to accelerate the repair of oxidative DNA damage by the base excision repair (BER) pathway, thereby enabling RAS-driven cancer cells to avoid senescence and continue to proliferate despite producing excess levels of reactive oxygen species. The carboxy-terminal domain of MYC, which is needed for heterodimerization with its MAX partner and DNA binding, is not required for the DNA repair activity of MYC. Ectopic expression of MYCΔCTD accelerates DNA repair, protects against RAS-induced senescence, and cooperates with RAS in the transformation of primary cells, whereas MYC mutants inactive in DNA repair exhibit weaker or no activity in these assays. These results demonstrate that the function of MYC in BER plays an important role in the MYC-RAS cooperation.
MYC和RAS癌基因早在非永生化原代细胞的转化以及转基因小鼠模型的肿瘤发展过程中就被发现具有协同作用。MYC可防止RAS诱导的衰老。此外，抑制MYC表达导致的肿瘤消退与细胞衰老相关。MYC如何防止RAS诱导的衰老以及肿瘤中MYC的抑制为何会导致衰老仍有待阐明。在此，我们表明MYC与Polβ DNA聚合酶相互作用并刺激其酶活性，以通过碱基切除修复（BER）途径加速氧化性DNA损伤的修复，从而使RAS驱动的癌细胞避免衰老，并尽管产生过量的活性氧仍能继续增殖。MYC与其MAX伙伴异二聚化和DNA结合所需的羧基末端结构域，对于MYC的DNA修复活性并非必需。MYCΔCTD的异位表达加速DNA修复，防止RAS诱导的衰老，并在原代细胞转化中与RAS协同作用，而在DNA修复中无活性的MYC突变体在这些试验中表现出较弱的活性或无活性。这些结果表明，MYC在BER中的功能在MYC-RAS协同作用中起重要作用。
