Nandi B, Talluri S, Kumar S, Yenumula C, Gold J S, Prabhala R, Munshi N C, Shammas M A
Harvard Medical School and Brigham and Women's Hospital, USA.
Researh Services, VA Healthcare System, West Roxbury, MA, USA.
J Transl Sci. 2019 Apr;5(2). doi: 10.15761/JTS.1000282. Epub 2018 Oct 1.
A variety of factors, whether extracellular (mutagens/carcinogens and viruses in the environment, chronic inflammation and radiation associated with the environment and/or electronic devices/machines) and/or intracellular (oxidative metabolites of food, oxidative stress due to inflammation, acid production, replication stress, DNA replication/repair errors, and certain hormones, cytokines, growth factors), pose a constant threat to the genomic integrity of a living cell. However, in the normal cellular environment multiple biological pathways including DNA repair, cell cycle, apoptosis and the immune system work in a precise, regulated (tightly controlled), timely and concerted manner to ensure genomic integrity, stability and proper functioning of a cell. If damage to DNA takes place, it is efficiently and accurately repaired by the DNA repair systems. Homologous recombination (HR) which utilizes either a homologous chromosome (in G1 phase) or a sister chromatid (in G2) as a template to repair the damage, is known to be the most precise repair system. HR in G2 which utilizes a sister chromatid as a template is also called an error free repair system. If DNA damage in a cell is so extensive that it overwhelms the repair system/s, the cell is eliminated by apoptosis. Thus, multiple pathways ensure that genome of a cell is intact and stable. However, constant exposure to DNA damage and/or dysregulation of DNA repair mechanism/s poses a risk of mutation and cancer. Oncogenesis, which seems to be a multistep process, is associated with acquisition of a number of genomic changes that enable a normal cell to progress from benign to malignant transformation. Transformed/cancer cells are recognized and killed by the immune system. However, the ongoing acquisition of new genomic changes enables cancer cells to survive/escape immune attack, evolve into a more aggressive phenotype, and eventually develop resistance to therapy. Although DNA repair (especially the HR) and the immune system play unique roles in preserving genomic integrity of a cell, they can also contribute to DNA damage, genomic instability and oncogenesis. The purpose of this article is to highlight the roles of DNA repair (especially HR) and the immune system in genomic evolution, with special focus on gastrointestinal cancer.
多种因素，无论是细胞外因素（环境中的诱变剂/致癌物和病毒、与环境和/或电子设备/机器相关的慢性炎症和辐射）还是细胞内因素（食物的氧化代谢产物、炎症引起的氧化应激、酸生成、复制应激、DNA复制/修复错误以及某些激素、细胞因子、生长因子），都对活细胞的基因组完整性构成持续威胁。然而，在正常细胞环境中，包括DNA修复、细胞周期、细胞凋亡和免疫系统在内的多种生物学途径以精确、受调控（严格控制）、及时且协同的方式发挥作用，以确保细胞的基因组完整性、稳定性和正常功能。如果发生DNA损伤，DNA修复系统会高效且准确地进行修复。同源重组（HR）利用同源染色体（在G1期）或姐妹染色单体（在G2期）作为模板来修复损伤，是已知最精确的修复系统。在G2期利用姐妹染色单体作为模板的HR也被称为无错修复系统。如果细胞中的DNA损伤过于广泛以至于超过了修复系统的能力，细胞会通过凋亡被清除。因此，多种途径确保细胞的基因组完整且稳定。然而，持续暴露于DNA损伤和/或DNA修复机制失调会带来突变和癌症的风险。肿瘤发生似乎是一个多步骤过程，与获得许多基因组变化相关，这些变化使正常细胞能够从良性转变为恶性。转化的/癌细胞会被免疫系统识别并杀死。然而，不断获得新的基因组变化使癌细胞能够存活/逃避免疫攻击，演变成更具侵袭性的表型，并最终产生对治疗的抗性。尽管DNA修复（尤其是HR）和免疫系统在维持细胞基因组完整性方面发挥着独特作用，但它们也可能导致DNA损伤、基因组不稳定和肿瘤发生。本文的目的是强调DNA修复（尤其是HR）和免疫系统在基因组进化中的作用，特别关注胃肠道癌。
