# RNAi, Histone Modification and the DDB1/CPSF-like Complex Rik1

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2020 · $422,400

## Abstract

Project Summary
Heterochromatin comprises tightly compacted repetitive regions of eukaryotic
chromosomes. It is inherited through mitosis and has roles in transcriptional silencing,
centromere specification and genome integrity, which profoundly impact epigenetic
mechanisms in health and disease. We have found that the epigenetic inheritance of
heterochromatin in the fission yeast S.pombe requires RNA interference (RNAi) to guide
histone modification, which occurs during the DNA replication phase of the cell cycle.
S.pombe centromeric repeats have an alternating arrangement of small RNA clusters
and origins of replication that makes collision of the transcription and replication
machineries all but inevitable. We found that RNAi promotes release of RNA polymerase
(Pol II) during S phase, allowing completion of DNA replication by the leading strand
DNA polymerase, which recruits the histone-modifying Rik1 complex to spread
heterochromatin along with DNA replication. In the absence of RNAi, stalled forks are
repaired by homologous recombination (HR) without histone modification, so that HR is
essential in the absence of RNAi, and reduces the copy number of rDNA repeats. This
model may explain the participation of non-coding RNA and DNA repair in many
examples of epigenetic silencing, such as imprinting and X-inactivation.
Recently, we have found that RNAi is essential for viability in quiescent cells (G0), which
are predominant in yeast and play critical roles in cancer, stem cells and neuronal
disease. Genetic screens have revealed that the Rik1 complex and Pol II are both
involved in this novel function for RNAi, implicating both heterochromatic silencing and
DNA repair. S.pombe is an outstanding model system for cell cycle research,
heterochromatic silencing, and RNAi. We will examine the roles of DNA replication,
RNA Polymerase release, DNA recombination and repair in heterochromatic histone
modification mediated by the Rik1 complex and RNAi.

## Key facts

- **NIH application ID:** 9965969
- **Project number:** 5R01GM076396-12
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** ROBERT A MARTIENSSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,400
- **Award type:** 5
- **Project period:** 2007-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965969

## Citation

> US National Institutes of Health, RePORTER application 9965969, RNAi, Histone Modification and the DDB1/CPSF-like Complex Rik1 (5R01GM076396-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965969. Licensed CC0.

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