論文 - 詳細
| RRC ID | 59572 |
|---|---|
| 著者 | Padeken J, Zeller P, Towbin B, Katic I, Kalck V, Methot SP, Gasser SM. |
| タイトル | Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression. |
| ジャーナル | Genes Dev |
| Abstract |
Caenorhabditis elegans has two histone H3 Lys9 methyltransferases, MET-2 (SETDB1 homolog) and SET-25 (G9a/SUV39H1 related). In worms, we found simple repeat sequences primarily marked by H3K9me2, while transposable elements and silent tissue-specific genes bear H3K9me3. RNA sequencing (RNA-seq) in histone methyltransferase (HMT) mutants shows that MET-2-mediated H3K9me2 is necessary for satellite repeat repression, while SET-25 silences a subset of transposable elements and tissue-specific genes through H3K9me3. A genome-wide synthetic lethality screen showed that RNA processing, nuclear RNA degradation, the BRCA1/BARD1 complex, and factors mediating replication stress survival are necessary for germline viability in worms lacking MET-2 but not SET-25. Unlike set-25 mutants, met-2-null worms accumulated satellite repeat transcripts, which form RNA:DNA hybrids on repetitive sequences, additively with the loss of BRCA1 or BARD1. BRCA1/BARD1-mediated H2A ubiquitination and MET-2 deposited H3K9me2 on satellite repeats are partially interdependent, suggesting both that the loss of silencing generates BRCA-recruiting DNA damage and that BRCA1 recruitment by damage helps silence repeats. The artificial induction of MSAT1 transcripts can itself trigger damage-induced germline lethality in a wild-type background, arguing that the synthetic sterility upon BRCA1/BARD1 and H3K9me2 loss is directly linked to the DNA damage provoked by unscheduled satellite repeat transcription. |
| 巻・号 | 33(7-8) |
| ページ | 436-451 |
| 公開日 | 2019-4-1 |
| DOI | 10.1101/gad.322495.118 |
| PII | gad.322495.118 |
| PMID | 30804228 |
| PMC | PMC6446544 |
| MeSH | Animals BRCA1 Protein / genetics* BRCA1 Protein / metabolism Caenorhabditis elegans / embryology* Caenorhabditis elegans / genetics* Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism Clustered Regularly Interspaced Short Palindromic Repeats DNA Transposable Elements / genetics Embryo, Nonmammalian Fertility / genetics Gene Expression Regulation, Developmental / genetics* Histone-Lysine N-Methyltransferase / genetics Histone-Lysine N-Methyltransferase / metabolism Histones / genetics* Microsatellite Repeats / genetics Mutation RNA Processing, Post-Transcriptional / genetics Temperature |
| IF | 8.99 |
| 引用数 | 6 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 11 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm1145 |