Alternative titles; symbols
HGNC Approved Gene Symbol: RIF1
Cytogenetic location: 2q23.3 Genomic coordinates (GRCh38) : 2:151,409,902-151,534,435 (from NCBI)
By searching a database for sequences similar to S. pombe and S. cerevisiae Rif1, Silverman et al. (2004) identified human RIF1. The deduced protein contains 2,472 amino acids. Alignment of the human, mouse, and fugu proteins revealed 2 conserved N-terminal regions and a conserved C-terminal region. The first 340 amino acids contain 8 armadillo-type repeats, which are helical folds that typically occur in long arrays, creating an extended curved protein or RNA interaction surface. RIF1 also contains a central serine-rich region and a bipartite nuclear localization signal within the C-terminal conserved region.
Yeast Rif1 associates with telomeres and regulates their length. In contrast, Silverman et al. (2004) found that human RIF1 did not accumulate at functional telomeres, but localized to dysfunctional telomeres and to telomeric DNA clusters in human ALT (alternative lengthening of telomeres) cell lines, which maintain telomeric DNA in the absence of telomerase. They noted that this pattern of telomere association is typical of DNA damage response factors. After induction of double-strand breaks in ALT cells, RIF1 formed foci that colocalized with other DNA damage response factors. This response was strictly dependent on ATM (607585) and 53BP1 (605230), but was not affected by diminished function of ATR (601215), BRCA1 (113705), CHK2 (604373), NBS1 (602667), or MRE11 (600814). RIF1 inhibition resulted in radiosensitivity and a defect in the intra-S-phase checkpoint. Silverman et al. (2004) concluded that RIF1 contributes to ATM-mediated protection against DNA damage.
Using mouse embryonic fibroblasts (MEFs), Cornacchia et al. (2012) found that Rif1 plays a role in replication timing. Epitope-tagged Rif1 was expressed in a dynamic and specific pattern during S phase. At mid-S phase, its expression clearly preceded the replication fork in pericentric heterochromatin. Deletion of Rif1 resulted in cells with significant fragmentation of replication domains into many smaller domains, chromatin simultaneously in early and middle stages of replication, defective chromatin repackaging after replication, and accumulation of p21 (CDKN1A; 116899), leading to a block at the G1/S transition. Deletion of Rif1 did not significantly alter transcription.
53BP1 is critical for the control of double-strand break (DSB) repair, promoting nonhomologous end-joining (NHEJ) and inhibiting the 5-prime end resection needed for homology-directed repair (HDR). Using dysfunctional telomeres and genomewide DSBs, Zimmermann et al. (2013) identified RIF1 as the main factor used by 53BP1 to impair 5-prime end resection. RIF1 inhibits resection involving CTIP (604124), BLM (604610), and EXO1 (606063), limits accumulation of BRCA1/BARD1 (601593) complexes at sites of DNA damage, and defines one of the mechanisms by which 53BP1 causes chromosomal abnormalities in BRCA1-deficient cells. Zimmermann et al. (2013) concluded that their data established RIF1 as an important contributor to the control of DSB repair by 53BP1.
Di Virgilio et al. (2013) identified RIF1 as an ATM phosphorylation-dependent interactor of 53BP1 and showed that absence of RIF1 results in 5-prime/3-prime DNA-end resection in mice. Consistent with enhanced DNA resection, RIF1 deficiency impairs DNA repair in the G1 and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs.
Boersma et al. (2015) identified MAD2L2 (604094) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres, and showed that MAD2L2 accumulates at uncapped telomeres and promotes NHEJ-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3-prime telomeric overhangs, indicating that MAD2L2 inhibits 5-prime end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1, and PTIP (608254). Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5-prime end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres, as MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8 (611685), RNF168 (612688), 53BP1, and RIF1, but not on PTIP, REV1 (606134), and REV3 (602776), the latter 2 acting with MAD2L2 in translesion synthesis. Boersma et al. (2015) concluded that their data established MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5-prime end resection downstream of RIF1.
Isobe et al. (2017) found that SCAI (619222) associated with 53BP1 and was recruited to ionizing radiation-induced foci (IRIF) in HeLa cells, thereby enhancing recruitment of BRCA1 to damage sites and facilitating HDR. The authors identified RIF1 as a determining factor to prevent accumulation of BRCA1 at IRIF. RIF1 immediately accumulated at damage sites upon DNA damage and associated with 53BP1. SCAI competed with RIF1 for 53BP1 binding and subsequently replaced RIF1, resulting in inhibition of RIF1 function, stimulation of BRCA1 accumulation at IRIF, and facilitation of HDR. Phosphorylation of 53BP1 played a critical role in its interaction with SCAI or RIF1. Phosphorylation of SP and TP (S/TP) sites in 53BP1 enhanced SCAI binding to 53BP1, whereas phosphorylation of SQ and TQ (S/TQ) sites in 53BP1 enhanced RIF1 binding to 53BP1.
Hartz (2014) mapped the RIF1 gene to chromosome 2q23.3 based on an alignment of the RIF1 sequence (GenBank AK001461) with the genomic sequence (GRCh38).
Boersma, V., Moatti, N., Segura-Bayona, S., Peuscher, M. H., van der Torre, J., Wevers, B. A., Orthwein, A., Durocher, D., Jacobs, J. J. L. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5-prime end resection. Nature 521: 537-540, 2015. [PubMed: 25799990] [Full Text: https://doi.org/10.1038/nature14216]
Cornacchia, D., Dileep, V., Quivy, J.-P., Roti, R., Tili, F., Santarella-Mellwig, R., Antony, C., Almouzni, G., Gilbert, D. M., Buonomo, S. B. C. Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells. EMBO J. 31: 3678-3690, 2012. [PubMed: 22850673] [Full Text: https://doi.org/10.1038/emboj.2012.214]
Di Virgilio, M., Callen, E., Yamane, A., Zhang, W., Jankovic, M., Gitlin, A. D., Feldhahn, N., Resch, W., Oliveria, T. Y., Chait, B. T., Nussenzweig, A., Casellas, R., Robbiani, D. F., Nussenzweig, M. C. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339: 711-715, 2013. [PubMed: 23306439] [Full Text: https://doi.org/10.1126/science.1230624]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/23/2014.
Isobe, S.-Y., Nagao, K., Nozaki, N., Kimura, H., Obuse, C. Inhibition of RIF1 by SCAI allows BRCA1-mediated repair. Cell Rep. 20: 297-307, 2017. [PubMed: 28700933] [Full Text: https://doi.org/10.1016/j.celrep.2017.06.056]
Silverman, J., Takai, H., Buonomo, S. B. C., Eisenhaber, F., de Lange, T. Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev. 18: 2108-2119, 2004. [PubMed: 15342490] [Full Text: https://doi.org/10.1101/gad.1216004]
Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A., de Lange, T. 53BP1 regulates DSB repair using Rif1 to control 5-prime end resection. Science 339: 700-704, 2013. [PubMed: 23306437] [Full Text: https://doi.org/10.1126/science.1231573]