Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated a novel cDNA encoding a peptide with 86% sequence homology to hSNF2L protein, a previously isolated human homologue of Drosophila ISWI. This gene, designated SMARCA5, contained an open reading frame of 3,156 nucleotides encoding a 1,052 amino-acid peptide (hSNF2H). As this product also revealed a significant (73%) identity in amino acid sequence to ISWI, a key component of chromatin-remodeling factors in Drosophila, hSNF2H may be another human homologue of this protein and, as such, could be involved in chromatin remodeling in humans. An ATPase domain characteristic of the SWI2/SNF2 family of proteins was highly conserved in ISWI, hSNF2L, and hSNF2H. Northern-blot analysis demonstrated ubiquitous expression of 5.1-kb and 4.1-kb transcripts of the hSNF2H gene. This gene was mapped by FISH to chromosome bands 4q31.1-->q31.2.
 ...
PMID:Cloning and mapping of SMARCA5 encoding hSNF2H, a novel human homologue of Drosophila ISWI. 973 Jun

Epigenetic reprogramming plays a pivotal role during embryogenesis, including both covalent and non-covalent modifications to chromatin. In this study, we investigated the role of SNF2 chromatin remodeling ATPases (SMARCA2 (previously known as BRAHMA), SMARCA4 (previously known as BRG1), SMARCA5 (previously known as SNF2H), SMARCA1 (previously known as SNF2L), CHD3, and CHD5) during porcine preimplantation embryonic development. Transcript levels for these ATPases change dynamically throughout development. We also investigated the effect of altering transcript levels of SMARCA2 and SMARCA4 via mRNA injection. Overexpression of SMARCA2 and SMARCA4 severely impaired embryo development. Results from these experiments show that embryos injected with SMARCA2 mRNA arrest between the four-cell and blastocyst stages. However, embryos injected with either wild-type SMARCA4 or a dominant negative variant or SMARCA4 arrest before zygotic genome activation. No differences in transcript abundance of SOX2, POU5F1, NANOG, and EIF1 (previously known as eIF1A) were detected after injection with SMARCA2 or its dominant negative variant at 48 h post-injection. Conversely, embryos injected with wild-type SMARCA4 and its dominant negative variant possessed altered expression of these genes. Examination of SNF2-type ATPase transcript abundance across all treatment groups revealed that only SMARCA1 was altered following injection with wild-type SMARCA2 and wild-type and dominant negative SMARCA4. We conclude that the arrest in porcine embryo development observed after injection is specific to the ATPase injected. Our data strongly support the hypothesis that SMARCA2 and SMARCA4 play different but fundamental roles controlling gene expression during early mammalian embryogenesis.
 ...
PMID:Manipulation of SMARCA2 and SMARCA4 transcript levels in porcine embryos differentially alters development and expression of SMARCA1, SOX2, NANOG, and EIF1. 1884 24

The regulation of nucleosome positioning and composition by ATP-dependent chromatin remodeling enzymes and their associated binding partners plays important biological roles in mammals. CECR2 is a binding partner to the ISWI (imitation switch) ATPase SNF2L/SMARCA1 and is involved in neural tube closure and inner ear development; however, its functions in adult tissues have not been examined. Here, we report that CECR2 contributes to spermatogenesis and forms a complex that includes the other ISWI ATPase SNF2H/SMARCA5 in the testis. Cecr2 mutant males non-penetrant for neural tube defects sired smaller litters than wild-type males. Strikingly, while we found that Cecr2 mutants have normal seminiferous epithelium morphology, sperm count, motility, and morphology, the mutant spermatozoa were compromised in their ability to fertilize oocytes. Investigation of CECR2/ISWI complexes in the testis showed that SNF2H interacted with CECR2, and this interaction was also observed in embryonic stem cells, suggesting that CECR2 may interact with SNF2H or SNF2L depending on the cell type. Finally, we found that Cecr2 mutants exhibit misregulation of the homeobox transcription factor Dlx5 in the testis, suggesting that CECR2 complexes may regulate gene expression during spermatogenesis. Taken together, our results demonstrate a novel role of CECR2-containing complexes in spermatogenesis and show that CECR2 interacts predominantly with SNF2H instead of SNF2L in the testis.
 ...
PMID:CECR2 is involved in spermatogenesis and forms a complex with SNF2H in the testis. 2288 7

The cellular response to ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) in native chromatin requires a tight coordination between the activities of DNA repair machineries and factors that modulate chromatin structure. SMARCA5 is an ATPase of the SNF2 family of chromatin remodeling factors that has recently been implicated in the DSB response. It forms distinct chromatin remodeling complexes with several non-canonical subunits, including the remodeling and spacing factor 1 (RSF1) protein. Despite the fact that RSF1 is often overexpressed in tumors and linked to tumorigenesis and genome instability, its role in the DSB response remains largely unclear. Here we show that RSF1 accumulates at DSB sites and protects human cells against IR-induced DSBs by promoting repair of these lesions through homologous recombination (HR) and non-homologous end-joining (NHEJ). Although SMARCA5 regulates the RNF168-dependent ubiquitin response that targets BRCA1 to DSBs, we found RSF1 to be dispensable for this process. Conversely, we found that RSF1 facilitates the assembly of centromere proteins CENP-S and CENP-X at sites of DNA damage, while SMARCA5 was not required for these events. Mechanistically, we uncovered that CENP-S and CENP-X, upon their incorporation by RSF1, promote assembly of the NHEJ factor XRCC4 at damaged chromatin. In contrast, CENP-S and CENP-X were dispensable for HR, suggesting that RSF1 regulates HR independently of these centromere proteins. Our findings reveal distinct functions of RSF1 in the 2 major pathways of DSB repair and explain how RSF1, through the loading of centromere proteins and XRCC4 at DSBs, promotes repair by non-homologous end-joining.
...
PMID:Remodeling and spacing factor 1 (RSF1) deposits centromere proteins at DNA double-strand breaks to promote non-homologous end-joining. 2397 6

Chromatin remodeling factors play an active role in the DNA damage response by shaping chromatin to facilitate the repair process. The spatiotemporal regulation of these factors is key to their function, yet poorly understood. We report that the structural nuclear protein NuMA accumulates at sites of DNA damage in a poly[ADP-ribose]ylation-dependent manner and functionally interacts with the ISWI ATPase SNF2h/SMARCA5, a chromatin remodeler that facilitates DNA repair. NuMA coimmunoprecipitates with SNF2h, regulates its diffusion in the nucleoplasm and controls its accumulation at DNA breaks. Consistent with NuMA enabling SNF2h function, cells with silenced NuMA exhibit reduced chromatin decompaction after DNA cleavage, lesser focal recruitment of homologous recombination repair factors, impaired DNA double-strand break repair in chromosomal (but not in episomal) contexts and increased sensitivity to DNA cross-linking agents. These findings reveal a structural basis for the orchestration of chromatin remodeling whereby a scaffold protein promotes genome maintenance by directing a remodeler to DNA breaks.
...
PMID:NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks. 2475 6

Chromatin compaction of deoxyribonucleic acid (DNA) presents a major challenge to the detection and removal of DNA damage. Helix-distorting DNA lesions that block transcription are specifically repaired by transcription-coupled nucleotide excision repair, which is initiated by binding of the CSB protein to lesion-stalled RNA polymerase II. Using live cell imaging, we identify a novel function for two distinct mammalian ISWI adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in resolving lesion-stalled transcription. Human ISWI isoform SMARCA5/SNF2H and its binding partners ACF1 and WSTF are rapidly recruited to UV-C induced DNA damage to specifically facilitate CSB binding and to promote transcription recovery. SMARCA5 targeting to UV-C damage depends on transcription and histone modifications and requires functional SWI2/SNF2-ATPase and SLIDE domains. After initial recruitment to UV damage, SMARCA5 re-localizes away from the center of DNA damage, requiring its HAND domain. Our studies support a model in which SMARCA5 targeting to DNA damage-stalled transcription sites is controlled by an ATP-hydrolysis-dependent scanning and proofreading mechanism, highlighting how SWI2/SNF2 chromatin remodelers identify and bind nucleosomes containing damaged DNA.
...
PMID:Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription. 2499 Mar 77

Members of the ISWI family of chromatin remodelers mobilize nucleosomes to control DNA accessibility and, in some cases, are required for recovery from DNA damage. However, it remains poorly understood how the non-catalytic ISWI subunits BAZ1A and BAZ1B might contact chromatin to direct the ATPase SMARCA5. Here, we find that the plant homeodomain of BAZ1A, but not that of BAZ1B, has the unusual function of binding DNA. Furthermore, the BAZ1A bromodomain has a non-canonical gatekeeper residue and binds relatively weakly to acetylated histone peptides. Using CRISPR-Cas9-mediated genome editing we find that BAZ1A and BAZ1B each recruit SMARCA5 to sites of damaged chromatin and promote survival. Genetic engineering of structure-designed bromodomain and plant homeodomain mutants reveals that reader modules of BAZ1A and BAZ1B, even when non-standard, are critical for DNA damage recovery in part by regulating ISWI factors loading at DNA lesions and supporting transcriptional programs required for survival.ISWI chromatin remodelers regulate DNA accessibility and have been implicated in DNA damage repair. Here, the authors uncover functions, in response to DNA damage, for the bromodomain of the ISWI subunit BAZ1B and for the non-canonical PHD and bromodomain modules of the paralog BAZ1A.
 ...
PMID:Non-canonical reader modules of BAZ1A promote recovery from DNA damage. 2902 63

ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion.
 ...
PMID:Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion. 3219 13