Synergistic lethality between BRCA1 and H3K9me2 loss reflects satellite derepression

Genes & Development
Jan PadekenSusan M Gasser

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 c...Continue Reading

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Citations

Feb 10, 2019·The Journal of Cell Biology·Colin E DelaneyJan Padeken
Sep 26, 2019·Frontiers in Molecular Biosciences·Ruth M Densham, Joanna R Morris
May 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Qian BianBarbara J Meyer
Jan 30, 2021·Nucleic Acids Research·Ivana MisovaSilvia Bagelova Polakova
Mar 5, 2021·Nature Communications·Maya SpichalShawn Ahmed
Apr 20, 2020·The Science of the Total Environment·Anye WamuchoOlga V Tsyusko
Apr 15, 2021·Molecular Cell·Rajani Kanth GudipatiHelge Großhans
Dec 7, 2020·Current Opinion in Genetics & Development·Rebecca E Brown, Catherine H Freudenreich
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Jul 3, 2021·Genes·Arjamand MushtaqTej K Pandita
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Jan 16, 2022·Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology·Faria Athar, Nicole M Templeman

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