Padeken, Jan; Zeller, Peter; Towbin, Benjamin; Katic, Iskra; Kalck, Veronique; Methot, Stephen P; Gasser, Susan M (2019). Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression. Genes & development, 33(7-8), pp. 436-451. Cold Spring Harbor Laboratory Press 10.1101/gad.322495.118
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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 mutants, -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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
08 Faculty of Science > Department of Biology > Institute of Cell Biology |
UniBE Contributor: |
Towbin, Benjamin Daniel |
Subjects: |
500 Science > 570 Life sciences; biology |
ISSN: |
0890-9369 |
Publisher: |
Cold Spring Harbor Laboratory Press |
Language: |
English |
Submitter: |
Benjamin Daniel Towbin |
Date Deposited: |
26 Nov 2020 15:15 |
Last Modified: |
05 Dec 2022 15:28 |
Publisher DOI: |
10.1101/gad.322495.118 |
PubMed ID: |
30804228 |
Uncontrolled Keywords: |
BRCA1 complex DNA repeats RNA:DNA hybrids genome instability heterochromatin histone H3K9 methylation satellite repeats transcriptional silencing |
BORIS DOI: |
10.7892/boris.130613 |
URI: |
https://boris.unibe.ch/id/eprint/130613 |
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