Alternative titles; symbols
HGNC Approved Gene Symbol: RMI1
Cytogenetic location: 9q21.32 Genomic coordinates (GRCh38): 9:83,980,359-84,004,074 (from NCBI)
RMI1 is a component of protein complexes that limit DNA crossover formation via the dissolution of double Holliday junctions (Raynard et al., 2006).
By mass spectrometric analysis of proteins associated with BLM (RECQL3; 604610) complexes purified from HeLa cells, followed by database analysis, Yin et al. (2005) identified RMI1, which they called BLAP75. The deduced 625-amino acid protein contains an N-terminal nucleic acid binding domain and a C-terminal domain conserved across several eukaryotic species. SDS-PAGE detected BLAP75 at an apparent molecular mass of 75 kD.
Yin et al. (2005) found that BLAP75 was associated with all 3 BLM-containing protein complexes immunopurified from HeLa cells. BLAP75 colocalized with BLM in subnuclear foci in response to DNA damage, and its depletion by small interfering RNA (siRNA) impaired the recruitment of BLM to these foci. Depletion of BLAP75 also resulted in deficient BLM phosphorylation during mitosis as well as defective cell proliferation. Cells depleted of BLAP75 displayed an increased level of sister-chromatid exchange, similar to cells depleted of BLM. Yin et al. (2005) concluded that BLAP75 is an essential component of the BLM-associated cellular machinery that maintains genome integrity.
BLM, together with topoisomerase III-alpha (TOP3A; 601243), can process recombination intermediates that contain double Holliday junctions into noncrossover products by a mechanism termed dissolution. Wu et al. (2006) showed that RMI1 promoted dissolution catalyzed by TOP3A in an vitro assay, but not dissolution catalyzed by other type IA topoisomerases. BLAP75 physically interacted with TOP3A, and it appeared to recruit TOP3A to double Holliday junctions. Raynard et al. (2006) showed that BLAP75 associated independently with both TOP3A and BLM, and that under physiologic conditions, dissolution of double Holliday junctions by BLM and TOP3A was completely dependent on BLAP75.
Xu et al. (2008) found that RMI1 and RMI2 (612426) were present in approximately stoichiometric amounts with other BLM complex components, including TOP3A, RPA (see RPA1; 179835), and BLAP250. RMI1 also associated with RMI2 and TOP3A in a second complex. RMI1 and RMI2 interacted directly, and both were essential for stability of the BLM complex. Depletion of either RMI1 or RMI2 depleted the other protein by 80 to 90%.
Sweetser et al. (2005) determined that the RMI1 gene contains 1 exon.
By genomic sequence analysis, Sweetser et al. (2005) mapped the RMI1 gene to chromosome 9q21.32
Associations Pending Confirmation
For discussion of a possible association between a Bloom syndrome-like disorder (see BLM, 210900) and variation in the RMI1 gene, see 610404.0001.
This variant is classified as a variant of unknown significance because its contribution to a Bloom syndrome-like disorder (see BLM, 210900) has not been confirmed.
In 2 first cousins from a consanguineous Turkish family (family 8) with microcephaly (-5 SD) and short stature (-3 to -4 SD), Martin et al. (2018) identified a homozygous 5-bp deletion (c.1255_1259del, NM_024945.2) in the RMI1 gene, predicted to result in a frameshift and premature termination (Lys419LeufsTer5). The mutation was found by whole-exome sequencing; the allele frequency was 1.1 x 10(-5). The mutation was not observed in homozygous state in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. Studies of sister chromatid exchange were not performed. One patient had mild developmental delay at age 7 years, and the other patient had normal development at age 13 years.
Martin, C.-A., Sarlos, K., Logan, C. V., Thakur, R. S., Parry, D. A., Bizard, A. H., Leitch, A., Cleal, L., Ali, N. S., Al-Owain, M. A., Allen, W., Altmuller, J., and 40 others. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am. J. Hum. Genet. 103: 221-231, 2018. Note: Erratum: Am. J. Hum. Genet. 103: 456 only, 2018. [PubMed: 30057030] [Full Text: https://doi.org/10.1016/j.ajhg.2018.07.001]
Raynard, S., Bussen, W., Sung, P. A double Holliday junction dissolvasome comprising BLM, topoisomerase III-alpha, and BLAP75. J. Biol. Chem. 281: 13861-13864, 2006. [PubMed: 16595695] [Full Text: https://doi.org/10.1074/jbc.C600051200]
Sweetser, D. A., Peniket, A. J., Haaland, C., Blomberg, A. A., Zhang, Y., Zaidi, S. T., Dayyani, F., Zhao, Z., Heerema, N. A., Boultwood, J., Dewald, G. W., Paietta, E., Slovak, M. L., Willman, C. L., Wainscoat, J. S., Bernstein, I. D., Daly, S. B. Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes Chromosomes Cancer 44: 279-291, 2005. [PubMed: 16015647] [Full Text: https://doi.org/10.1002/gcc.20236]
Wu, L., Bachrati, C. Z., Ou, J., Xu, C., Yin, J., Chang, M., Wang, W., Li, L., Brown, G. W., Hickson, I. D. BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates. Proc. Nat. Acad. Sci. 103: 4068-4073, 2006. [PubMed: 16537486] [Full Text: https://doi.org/10.1073/pnas.0508295103]
Xu, D., Guo, R., Sobeck, A., Bachrati, C. Z., Yang, J., Enomoto, T., Brown, G. W., Hoatlin, M. E., Hickson, I. D., Wang, W. RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 22: 2843-2855, 2008. [PubMed: 18923082] [Full Text: https://doi.org/10.1101/gad.1708608]
Yin, J., Sobeck, A., Xu, C., Meetei, A. R., Hoatlin, M., Li, L., Wang, W. BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity. EMBO J. 24: 1465-1476, 2005. [PubMed: 15775963] [Full Text: https://doi.org/10.1038/sj.emboj.7600622]