复制时间(RT)是一种细胞程序,用于协调基因组中所有起点的DNA复制的启动。RIF1(复制时序调节因子1)是人细胞中RT的主要调节因子。RIF1的这种作用与结合G4-四链体和3D染色质的变化有关,这可能会在长距离上抑制起源激活。RIF1与TP53BP1(肿瘤蛋白p53结合蛋白)的相互作用强调了RIF1在叉再激活和DNA双链(DSB)修复(DSBR)中的许多作用。在G1中,RIF1拮抗BRCA1(BRCA1DNA修复相关),抑制末端切除和同源重组修复(HRR)并促进非同源末端连接(NHEJ),有助于DSBR途径选择。RIF1是S内检查点的重要元素,可以在HRR的参与下恢复损坏的复制叉。高分辨率显微镜研究表明,RIF1与TP53BP1合作,以保留被DSB破坏的基因组基因座的3D结构和表观遗传标记。除了TP53BP1,RIF1与许多其他蛋白质相互作用,包括参与DNA损伤反应的蛋白质,细胞周期调节,和染色质重塑。作为受损的RT,DSBR和fork再激活与基因组不稳定性有关,恶性转化的标志,RIF1有一个诊断,预后,和癌症的治疗潜力。进一步的研究可能会揭示RT共同调节的其他方面,DSBR,和RIF1重新激活叉。
Replication timing (RT) is a cellular program to coordinate initiation of DNA replication in all origins within the genome. RIF1 (replication timing regulatory factor 1) is a master regulator of RT in human cells. This role of RIF1 is associated with binding G4-quadruplexes and changes in 3D chromatin that may suppress origin activation over a long distance. Many effects of RIF1 in fork reactivation and DNA double-strand (DSB) repair (DSBR) are underlined by its interaction with
TP53BP1 (tumor protein p53 binding protein). In G1, RIF1 acts antagonistically to BRCA1 (BRCA1 DNA repair associated), suppressing end resection and homologous recombination repair (HRR) and promoting non-homologous end joining (NHEJ), contributing to DSBR pathway choice. RIF1 is an important element of intra-S-checkpoints to recover damaged replication fork with the involvement of HRR. High-resolution microscopic studies show that RIF1 cooperates with
TP53BP1 to preserve 3D structure and epigenetic markers of genomic loci disrupted by DSBs. Apart from
TP53BP1, RIF1 interact with many other proteins, including proteins involved in DNA damage response, cell cycle regulation, and chromatin remodeling. As impaired RT, DSBR and fork reactivation are associated with genomic instability, a hallmark of malignant transformation, RIF1 has a diagnostic, prognostic, and therapeutic potential in cancer. Further studies may reveal other aspects of common regulation of RT, DSBR, and fork reactivation by RIF1.