Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland.
Int J Mol Sci. 2021 Oct 23;22(21):11440. doi: 10.3390/ijms222111440.
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.
复制定时 (RT) 是一种细胞程序，用于协调基因组中所有起点的 DNA 复制起始。RIF1（复制定时调节因子 1）是人类细胞中 RT 的主要调节因子。RIF1 的这种作用与其结合 G4-四链体和 3D 染色质变化有关，这些变化可能抑制远距离的起始激活。RIF1 在叉重组和 DNA 双链断裂 (DSBR) 修复 (DSBR) 中的许多作用都因其与 TP53BP1（肿瘤蛋白 p53 结合蛋白）的相互作用而得到强调。在 G1 期，RIF1 与 BRCA1（BRCA1 相关的 DNA 修复）拮抗，抑制末端切除和同源重组修复 (HRR)，促进非同源末端连接 (NHEJ)，有助于 DSBR 途径的选择。RIF1 是内 S 检查点的重要组成部分，通过 HRR 恢复受损的复制叉。高分辨率显微镜研究表明，RIF1 与 TP53BP1 合作，以维持 3D 结构和基因组位点的表观遗传标记，这些位点被 DSB 破坏。除了 TP53BP1，RIF1 还与许多其他蛋白质相互作用，包括参与 DNA 损伤反应、细胞周期调节和染色质重塑的蛋白质。由于受损的 RT、DSBR 和叉重组与基因组不稳定性有关，而基因组不稳定性是恶性转化的标志，因此 RIF1 在癌症的诊断、预后和治疗方面具有潜力。进一步的研究可能会揭示 RIF1 对 RT、DSBR 和叉重组的共同调节的其他方面。
