Rixosomal RNA degradation contributes to silencing of Polycomb target genes

Haining Zhou, Chad B. Stein, Tiasha A. Shafiq, Gergana Shipkovenska, Marian Kalocsay, Joao A. Paulo, Jiuchun Zhang, Zhenhua Luo, Steven P. Gygi, Karen Adelman and Danesh Moazed ()
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Haining Zhou: Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Chad B. Stein: Blavatnik Institute, Harvard Medical School
Tiasha A. Shafiq: Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Gergana Shipkovenska: Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Marian Kalocsay: Blavatnik Institute, Harvard Medical School
Joao A. Paulo: Blavatnik Institute, Harvard Medical School
Jiuchun Zhang: Blavatnik Institute, Harvard Medical School
Zhenhua Luo: the First Affiliated Hospital, Sun Yat-sen University
Steven P. Gygi: Blavatnik Institute, Harvard Medical School
Karen Adelman: Blavatnik Institute, Harvard Medical School
Danesh Moazed: Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School

Nature, 2022, vol. 604, issue 7904, 167-174

Abstract: Abstract Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are histone-modifying and -binding complexes that mediate the formation of facultative heterochromatin and are required for silencing of developmental genes and maintenance of cell fate1–3. Multiple pathways of RNA decay work together to establish and maintain heterochromatin in fission yeast, including a recently identified role for a conserved RNA-degradation complex known as the rixosome or RIX1 complex4–6. Whether RNA degradation also has a role in the stability of mammalian heterochromatin remains unknown. Here we show that the rixosome contributes to silencing of many Polycomb targets in human cells. The rixosome associates with human PRC complexes and is enriched at promoters of Polycomb target genes. Depletion of either the rixosome or Polycomb results in accumulation of paused and elongating RNA polymerase at Polycomb target genes. We identify point mutations in the RING1B subunit of PRC1 that disrupt the interaction between PRC1 and the rixosome and result in diminished silencing, suggesting that direct recruitment of the rixosome to chromatin is required for silencing. Finally, we show that the RNA endonuclease and kinase activities of the rixosome and the downstream XRN2 exoribonuclease, which degrades RNAs with 5′ monophosphate groups generated by the rixosome, are required for silencing. Our findings suggest that rixosomal degradation of nascent RNA is conserved from fission yeast to human, with a primary role in RNA degradation at facultative heterochromatin in human cells.

Date: 2022
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DOI: 10.1038/s41586-022-04598-0

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