载脂蛋白BmRNA编辑催化多肽样(APOBEC)家族的酶是在DNA和RNA中将胞嘧啶转化为尿嘧啶的胞嘧啶脱氨酶。在这些蛋白质中,APOBEC3亚家族成员,APOBEC3A(A3A)和APOBEC3B(A3B),是癌细胞突变的主要来源。癌细胞中A3A和A3B的异常表达导致具有特定单碱基取代(SBS)特征的突变积累,以C→T和C→G变化为特征,在许多肿瘤类型中。除了助长诱变,A3A和A3B,特别是A3A,诱导DNA复制应激,DNA损伤,通过它们的催化活性和染色体的不稳定性,触发一系列细胞反应。因此,A3A/B已成为癌症发展过程中基因组进化的关键驱动因素,有助于肿瘤发生,肿瘤异质性,和治疗抗性。然而,A3A/B在癌细胞中的表达呈现了可用于治疗的癌症脆弱性。在这次审查中,我们讨论了最近的研究,阐明了调节A3A表达的机制和A3A在癌症中的影响。我们还回顾了A3A抑制剂的最新进展,并对A3A的未来研究方向进行了展望。
Enzymes of the apolipoprotein B mRNA editing catalytic polypeptide like (APOBEC) family are cytosine deaminases that convert cytosine to uracil in DNA and RNA. Among these proteins, APOBEC3 sub-family members, APOBEC3A (A3A) and APOBEC3B (A3B), are prominent sources of mutagenesis in cancer cells. The aberrant expression of A3A and A3B in cancer cells leads to accumulation of mutations with specific single-base substitution (SBS) signatures, characterized by C→T and C→G changes, in a number of tumor types. In addition to fueling mutagenesis, A3A and A3B, particularly A3A, induce DNA replication stress, DNA damage, and chromosomal instability through their catalytic activities, triggering a range of cellular responses. Thus, A3A/B have emerged as key drivers of genome evolution during cancer development, contributing to tumorigenesis, tumor heterogeneity, and therapeutic resistance. Yet, the expression of A3A/B in cancer cells presents a cancer vulnerability that can be exploited therapeutically. In this review, we discuss the recent studies that shed light on the mechanisms regulating A3A expression and the impact of A3A in cancer. We also review recent advances in the development of A3A inhibitors and provide perspectives on the future directions of A3A research.