HGNC Approved Gene Symbol: ZNF827
Cytogenetic location: 4q31.21-q31.22 Genomic coordinates (GRCh38): 4:145,757,627-145,938,823 (from NCBI)
Telomeric maintenance is performed by either the enzyme telomerase (see 187270) or the alternative lengthening of telomeres (ALT) pathway, which uses homologous recombination (HR)-mediated replication to synthesize new telomeric DNA. ZNF827 is a zinc finger protein that regulates ALT by binding nuclear receptors and recruiting the nucleosome remodeling and histone deacetylation (NURD) complex to telomeres to induce HR (Conomos et al., 2014).
Conomos et al. (2014) reported that ZNF827 has an N-terminal RRK motif for interaction with the NURD complex.
Using overexpression and small interfering RNA (siRNA)-mediated knockdown experiments in human WI38-VA13/2RA ALT cells and HT1080 telomerase-positive cells, Conomos et al. (2014) showed that ZNF827 recruited NURD to telomeric DNA. ZNF827 with a mutated RRK motif retained its ability to bind telomeres, but it did not recruit NURD. Immunofluorescence analysis confirmed that NURD recruitment was specific to ALT telomeres and required the RRK motif of ZNF827. Immunoprecipitation analysis showed that ZNF827 interacted directly with many NURD components, but not with LSD1 (KDM1A; 609132). Knockdown of nuclear receptors TR4 (NR2C2; 601426) and/or COUPTF2 (NR2F2; 107773), but not TR2 (NR2C1; 601529), led to decreased recruitment of ZNF827 to telomeres. TR4 expression was inversely correlated with ZNF827 expression, suggesting that TR4 is a negative regulator of ZNF827. Telomere chromatin immunoprecipitation analysis revealed that binding of ZNF827 to telomeres throughout the cell cycle was similar to that of NURD, and that NURD binding at telomeres was inversely correlated with ZNF827 expression. Knockdown and overexpression experiments showed that ZNF827 expression correlated positively with the prevalence of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) and other telomeric aberrations. ZNF827 expression correlated inversely with binding of shelterin components (e.g., TERF2; 602027) to telomeres and with histone H4 (see 602822) acetylation, the latter of which was dependent on the RRK motif. ZNF827 overexpression led to increased DNA synthesis at telomeres and recruitment of HR proteins, such as BRIT1 (MCPH1; 607117) and BRCA1 (113705). Expression of ZNF827 correlated with the frequency of 'telomere bridges,' or stretches of telomeric DNA forming connections between telomeres, and this relationship was independent of the RRK motif and ALT activity. The number of telomere bridges increased further in ZNF827-overexpressing cells treated with HDAC inhibitors. In ZNF827-overexpressing cells, the most telomere bridges and accumulation of cells occurred in G2-M phase, suggesting delayed cell-cycle progression. ZNF827 depletion led to decreased growth of ALT cells, but not telomerase-positive cells, with an increase in senescent and nonviable cells, as well as in cleaved caspase-3 (CASP3; 606636)-positive cells. ZNF827 expression correlated inversely with phosphorylated histone H2A (see 613499) in ALT cells, but not in telomerase-positive cells, suggesting that ZNF827 inhibits the DNA damage response in ALT cells.
Gross (2018) mapped the ZNF827 gene to chromosome 4q31.21-q31.22 based on an alignment of the ZNF827 sequence (GenBank BC117407) with the genomic sequence (GRCh38).
Conomos, D., Reddel, R. R., Pickett, H. A. NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination. Nature Struct. Molec. Biol. 21: 760-770, 2014. [PubMed: 25150861] [Full Text: https://doi.org/10.1038/nsmb.2877]
Gross, M. B. Personal Communication. Baltimore, Md. 5/4/2018.