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METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148573 | GEO | 2020/04/14

REPOSITORIES: GEO

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Similar Datasets

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [other]

Project description:Examination of R-loop formation at I-PpoI cutting site (28S rDNA and DAB1) and other uncut genome in NC or siMETTL3 transferred HEK293T with or without I-PpoI cutting

2020-04-14 | GSE148571 | GEO

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [RIP-Seq]

Project description:The goals of this study are to compare the level of YTHDC1 associated nascent RNA at chromatin between DMSO and zeocin treatment.

2020-04-13 | GSE148572 | GEO

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation

Project description:METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation

| PRJNA625048 | ENA

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [other]

Project description:METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [other]

| PRJNA625049 | ENA

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [RIP-Seq]

Project description:METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [RIP-Seq]

| PRJNA625054 | ENA

DNA-RNA hybrids at DSBs interfere with repair by homologous recombination.

Project description:DNA double-strand breaks (DSBs) are the most harmful DNA lesions and their repair is crucial for cell viability and genome integrity. The readout of DSB repair may depend on whether DSBs occur at transcribed versus non-transcribed regions. Some studies have postulated that DNA-RNA hybrids form at DSBs to promote recombinational repair, but others have challenged this notion. To directly assess whether hybrids formed at DSBs promote or interfere with the recombinational repair, we have used plasmid and chromosomal-based systems for the analysis of DSB-induced recombination in Saccharomyces cerevisiae. We show that, as expected, DNA-RNA hybrid formation is stimulated at DSBs. In addition, mutations that promote DNA-RNA hybrid accumulation, such as hpr1∆ and rnh1∆ rnh201∆, cause high levels of plasmid loss when DNA breaks are induced at sites that are transcribed. Importantly, we show that high levels or unresolved DNA-RNA hybrids at the breaks interfere with their repair by homologous recombination. This interference is observed for both plasmid and chromosomal recombination and is independent of whether the DSB is generated by endonucleolytic cleavage or by DNA replication. These data support a model in which DNA-RNA hybrids form fortuitously at DNA breaks during transcription and need to be removed to allow recombinational repair, rather than playing a positive role.

| S-EPMC8289408 | biostudies-literature

Homologous recombination-dependent repair of telomeric DSBs in proliferating human cells.

Project description:Telomeres prevent chromosome ends from being recognized as double-stranded breaks (DSBs). Meanwhile, G/C-rich repetitive telomeric DNA is susceptible to attack by DNA-damaging agents. How cells balance the need to protect DNA ends and the need to repair DNA lesions in telomeres is unknown. Here we show that telomeric DSBs are efficiently repaired in proliferating cells, but are irreparable in stress-induced and replicatively senescent cells. Using the CRISPR-Cas9 technique, we specifically induce DSBs at telomeric or subtelomeric regions. We find that DSB repair (DSBR) at subtelomeres occurs in an error-prone manner resulting in small deletions, suggestive of NHEJ. However, DSBR in telomeres involves 'telomere-clustering', 3'-protruding C-rich telomeric ssDNA, and HR between sister-chromatid or interchromosomal telomeres. DSBR in telomeres is suppressed by deletion or inhibition of Rad51. These findings reveal proliferation-dependent DSBR in telomeres and suggest that telomeric HR, which is normally constitutively suppressed, is activated in the context of DSBR.

| S-EPMC4942568 | biostudies-literature

N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication.

Project description:N6-methyladenosine (m6A) constitutes one of the most abundant internal RNA modifications and is critical for RNA metabolism and function. It has been previously reported that viral RNA contains internal m6A modifications; however, only recently the function of m6A modification in viral RNAs has been elucidated during infections of HIV, hepatitis C virus and Zika virus. In the present study, we found that enterovirus 71 (EV71) RNA undergoes m6A modification during viral infection, which alters the expression and localization of the methyltransferase and demethylase of m6A, and its binding proteins. Moreover, knockdown of m6A methyltransferase resulted in decreased EV71 replication, whereas knockdown of the demethylase had the opposite effect. Further study showed that the m6A binding proteins also participate in the regulation of viral replication. In particular, two m6A modification sites were identified in the viral genome, of which mutations resulted in decreased virus replication, suggesting that m6A modification plays an important role in EV71 replication. Notably, we found that METTL3 interacted with viral RNA-dependent RNA polymerase 3D and induced enhanced sumoylation and ubiquitination of the 3D polymerase that boosted viral replication. Taken together, our findings demonstrated that the host m6A modification complex interacts with viral proteins to modulate EV71 replication.

| S-EPMC6326802 | biostudies-literature

The RNA N6-Methyladenosine Methyltransferase METTL3 Promotes the Progression of Kidney Cancer via N6-Methyladenosine-Dependent Translational Enhancement of ABCD1.

Project description:The role of N6-methyladenosine (m6A)-modifying proteins in cancer progression depends on the cell type and mRNA affected. However, the biological role and underlying mechanism of m6A in kidney cancer is limited. Here, we discovered the variability in m6A methyltransferase METTL3 expression was significantly increased in clear cell renal cell carcinoma (ccRCC) the most common subtype of renal cell carcinoma (RCC), and high METTL3 expression predicts poor prognosis in ccRCC patients using a dataset from The Cancer Genome Atlas (TCGA). Importantly, knockdown of METTL3 in ccRCC cell line impaired both cell migration capacity and tumor spheroid formation in soft fibrin gel, a mechanical method for selecting stem-cell-like tumorigenic cells. Consistently, overexpression of METTL3 but not methyltransferase activity mutant METTL3 can promote cell migration, spheroid formation in cell line and tumor growth in xenograft model. Transcriptional profiling of m6A in ccRCC tissues identified the aberrant m6A transcripts were enriched in cancer-related pathways. Further m6A-sequencing of METTL3 knockdown cells and functional studies confirmed that translation of ABCD1, an ATP-binding cassette (ABC) transporter of fatty acids, was inhibited by METTL3 in m6A-dependent manner. Moreover, knockdown of ABCD1 in ccRCC cells decreased cancer cell migration and spheroid formation, and upregulation of ABCD1 acts as an adverse prognosis factor of kidney cancer patients. In summary, our study identifies that METTL3 promotes ccRCC progression through m6A modification-mediated translation of ABCD1, providing an epitranscriptional insight into the molecular mechanism in kidney cancer.

| S-EPMC8496489 | biostudies-literature

METTL3-Dependent N6-Methyladenosine Modification Programs Human Neural Progenitor Cell Proliferation.

Project description:METTL3, a methyltransferase responsible for N6-methyladenosine (m6A) modification, plays key regulatory roles in mammal central neural system (CNS) development. However, the specific epigenetic mechanisms governing human CNS development remain poorly elucidated. Here, we generated small-molecule-assisted shut-off (SMASh)-tagged hESC lines to reduce METTL3 protein levels, and found that METTL3 is not required for human neural progenitor cell (hNPC) formation and neuron differentiation. However, METTL3 deficiency inhibited hNPC proliferation by reducing SLIT2 expression. Mechanistic studies revealed that METTL3 degradation in hNPCs significantly decreased the enrichment of m6A in SLIT2 mRNA, consequently reducing its expression. Our findings reveal a novel functional target (SLIT2) for METTL3 in hNPCs and contribute to a better understanding of m6A-dependent mechanisms in hNPC proliferation.

| S-EPMC10647291 | biostudies-literature

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