Alternative titles; symbols
HGNC Approved Gene Symbol: ESCO1
Cytogenetic location: 18q11.2 Genomic coordinates (GRCh38) : 18:21,529,284-21,600,704 (from NCBI)
ESCO1 belongs to a conserved family of acetyltransferases involved in sister chromatid cohesion (Hou and Zou, 2005).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned ESCO1, which they designated KIAA1911. The deduced protein contains 864 amino acids. RT-PCR ELISA detected intermediate ESCO1 expression in all adult and fetal tissues and specific brain regions examined.
By searching an EST database for sequences similar to yeast Ctf7, a protein necessary for sister chromatid cohesion, Bellows et al. (2003) identified ESCO1, which they called EFO1. The deduced 840-amino acid protein has 2 N-terminal domains similar to delta- and beta-type linker histone proteins and a C-terminal domain similar to the core domain of Ctf7. Northern blot analysis detected an EFO1 transcript in most human tissues tested, with elevated expression in skeletal muscle. Fluorescence-tagged EFO1 localized to nuclei of transfected HeLa cells.
By searching databases for human proteins similar to yeast and fly proteins involved in sister chromatid cohesion, Hou and Zou (2005) identified EFO1. The C-terminal half of the deduced protein contains a C2H2 zinc finger and a putative acetyltransferase domain. Within this region, EFO1 shares 59% amino acid identity with EFO2 (ESCO2; 609353). In contrast, the N-terminal half of EFO1 shares little similarity with EFO2 or with the yeast and fly homologs.
Bellows et al. (2003) found that bacterially expressed human EFO1 exhibited autoacetylation activity. Deletion of the C-terminal Ctf7 core domain resulted in an inactive protein.
Hou and Zou (2005) found that the C-terminal half of EFO1 possessed autoacetylation activity, and mutation of conserved residues within the acetyltransferase domain reduced autoacetylation. RNA interference in HeLa cells showed that EFO1 was required for sister chromatid cohesion. There was a significant increase in mitotic cells with unpaired chromatids (67%) when EFO1 was depleted and a further increase in unpaired chromatids (93%) when both EFO1 and EFO2 were reduced simultaneously. Depletion of EFO1 or EFO2 resulted in an enrichment in G2/M cells, an increase in cells with chromosomes scattered along spindles, and an increase in cells with multipole spindles. However, depletion of EFO1 or EFO2 had no effect on the binding of cohesin (see 606462) with chromosomes in interphase cells. All cellular effects were exacerbated in cells depleted of both EFO1 and EFO2. In HeLa and 293T human embryonic kidney cells, about 70% of endogenous EFO1 and EFO2 associated with chromosomes, but the 2 proteins were differentially regulated during the cell cycle. EFO1 remained on chromosomes in mitosis, whereas EFO2 dissociated from chromosomes and/or was degraded. Mutation analysis indicated that binding of EFO1 or EFO2 to chromosomes was mediated by their diverse N termini.
Cohesion between sister chromatids is thought to be generated only during ongoing DNA replication by an obligate coupling between cohesion establishment factors such as Eco1 (Ctf7) and the replisome. Using budding yeast, Unal et al. (2007) challenged this model by showing that cohesion is generated by an Eco1-dependent but replication-independent mechanism in response to double-strand breaks in G2/M. Furthermore, their studies revealed that Eco1 has 2 functions: a cohesive activity and a conserved acetyltransferase activity, which triggers the generation of cohesion in response to double-strand breaks and the DNA damage checkpoint. Finally, the double-strand break-induced cohesion is not limited to broken chromosomes but occurs also on unbroken chromosomes, suggesting that the DNA damage checkpoint through Eco1 provides genomewide protection of chromosome integrity.
Rolef Ben-Shahar et al. (2008) identified spontaneous suppressors of the thermosensitive eco1-1 allele in budding yeast. An acetylation-mimicking mutation of a conserved lysine in cohesin's Smc3 (606062) subunit makes Eco1 dispensable for cell growth, and Rolef Ben-Shahar et al. (2008) showed that Smc3 is acetylated in an Eco1-dependent manner during DNA replication to promote sister chromatid cohesion. A second set of eco1-1 suppressors inactivate the budding yeast ortholog of the cohesin destabilizer Wapl (610754). Rolef Ben-Shahar et al. (2008) concluded that Eco1 modifies cohesin to stabilize sister chromatid cohesion in parallel with a cohesion establishment reaction that is in principle Eco1-independent.
Unal et al. (2008) found that in budding yeast, the head domain of the Smc3 protein subunit of cohesin is acetylated by the Eco1 protein acetyltransferase at 2 evolutionarily conserved residues, promoting the chromatin-bound cohesin to tether sister chromatids. Smc3 protein acetylation is induced in S phase after the chromatin loading of cohesin and is suppressed in G1 and G2/M.
Zhang et al. (2008) showed that acetylation of SMC3 by ESCO1 was required for S phase sister chromatid cohesion in human cells and in yeast. In HeLa cells, ESCO1 acetylated SMC3 on lys105 and lys106, and knockdown of ESCO1 expression via small interfering RNA significantly decreased SMC3 acetylation. Expression of a dominant-negative nonacetylatable SMC3 mutant in HEK293T cells permitted SMC3 incorporation into the cohesin complex, but it interfered with sister chromatid cohesion and resulted in scattered chromosomes and chromosome breakage. Zhang et al. (2008) concluded that ESCO1 is the major acetyltransferase required for SMC3 acetylation, and that SMC3 acetylation is required for sister chromatid cohesion and maintenance of genomic stability.
Through single-molecule analysis, Terret et al. (2009) demonstrated that a replication complex, the RFC-CTF18 clamp loader (see 613201), controls the velocity spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin's SMC3 subunit and sister chromatid cohesion. Unexpectedly, Terret et al. (2009) discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (including those derived from Roberts syndrome (268300) patients, in whom ESCO2 is biallelically mutated), and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin's hyperstable interaction with 2 regulatory cofactors, WAPL and PDS5A (613200); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFC-CTF18. Terret et al. (2009) concluded that their results showed a novel mechanism for clamp loader-dependent fork progression, mediated by the posttranslational modification and structural remodeling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts syndrome cohesinopathy.
By genomic sequence analysis, Nagase et al. (2001) mapped the ESCO1 gene to chromosome 18.
Bellows, A. M., Kenna, M. A., Cassimeris, L., Skibbens, R. V. Human EFO1p exhibits acetyltransferase activity and is a unique combination of linker histone and Ctf7p/Eco1p chromatid cohesion establishment domains. Nucleic Acids Res. 31: 6334-6343, 2003. [PubMed: 14576321] [Full Text: https://doi.org/10.1093/nar/gkg811]
Hou, F., Zou, H. Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister-chromatid cohesion. Molec. Biol. Cell 16: 3908-3918, 2005. [PubMed: 15958495] [Full Text: https://doi.org/10.1091/mbc.e04-12-1063]
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA Res. 8: 179-187, 2001. [PubMed: 11572484] [Full Text: https://doi.org/10.1093/dnares/8.4.179]
Rolef Ben-Shahar, T. R., Heeger, S., Lehane, C., East, P., Flynn, H., Skehel, M., Uhlmann, F. Eco1-dependent cohesin acetylation during establishment of sister chromatid cohesion. Science 321: 563-566, 2008. [PubMed: 18653893] [Full Text: https://doi.org/10.1126/science.1157774]
Terret, M.-E., Sherwood, R., Rahman, S., Qin, J., Jallepalli, P. V. Cohesin acetylation speeds the replication fork. Nature 462: 231-234, 2009. [PubMed: 19907496] [Full Text: https://doi.org/10.1038/nature08550]
Unal, E., Heidinger-Pauli, J. M., Kim, W., Guacci, V., Onn, I., Gygi, S. P., Koshland, D. E. A molecular determinant for the establishment of sister chromatid cohesion. Science 321: 566-569, 2008. [PubMed: 18653894] [Full Text: https://doi.org/10.1126/science.1157880]
Unal, E., Heidinger-Pauli, J. M., Koshland, D. DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science 317: 245-248, 2007. Note: Erratum: Science 318: 1722 only, 2007. [PubMed: 17626885] [Full Text: https://doi.org/10.1126/science.1140637]
Zhang, J., Shi, X., Li, Y., Kim, B.-J., Jia, J., Huang, Z., Yang, T., Fu, X., Jung, S. Y., Wang, Y., Zhang, P., Kim, S.-T., Pan, X., Qin, J. Acetylation of Smc3 by Eco1 is required for S phase sister chromatid cohesion in both human and yeast. Molec. Cell 31: 143-151, 2008. [PubMed: 18614053] [Full Text: https://doi.org/10.1016/j.molcel.2008.06.006]