Abstract
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.
Highlights
Replication timing (RT) is a cellular program to coordinate DNA replication initiations in different chromosomal regions
We present and update information on RIF1 structure and functions in RT, replication fork reactivation, and choice and mechanisms of DSBs repair (DSBR)
We provide some data and arguments supporting the hypothesis that RIF1 may regulate RT and DSBR in mutually related mechanisms
Summary
Replication timing (RT) is a cellular program to coordinate DNA replication initiations in different chromosomal regions (reviewed in [1]). It is clear that impaired DNA replication from a single origin impairs RT, if not resumed in an appropriate time This resuming may be associated with the generation of DSBs as an intermediate of fork repair process. Replication timing regulatory factor 1 (RIF1, RAP1-interacting factor 1) is a key regulator of RT and plays a role in DSBR choice, so it is a candidate to adjust DSBR to RT [6,7] Apart from these activities, RIF1 can be involved in several other processes, including nuclear organization, regulation of telomerase and telomere maintenance, transcriptional regulation of gene clusters, regulation of stem cell pluripotency, and resolution of ultrafine. We present and update information on RIF1 structure and functions in RT, replication fork reactivation, and choice and mechanisms of DSBR. We tried to focus on the mammalian, especially human, RIF1, but due to the still incomplete knowledge on RIF1 functions, sometimes data obtained in yeast are provided
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