Drosophila SUMM4 complex couples insulator function and DNA replication control

  1. Evgeniya N Andreyeva
  2. Alexander V Emelyanov
  3. Markus Nevil
  4. Lu Sun
  5. Elena Vershilova
  6. Christina A Hill
  7. Michael-C Keogh
  8. Robert J Duronio
  9. Arthur I Skoultchi
  10. Dmitry V Fyodorov  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. University of North Carolina at Chapel Hill, United States
  3. EpiCypher, United States

Abstract

Asynchronous replication of chromosome domains during S phase is essential for eukaryotic genome function, but the mechanisms establishing which domains replicate early versus late in different cell types remain incompletely understood. Intercalary heterochromatin domains replicate very late in both diploid chromosomes of dividing cells and in endoreplicating polytene chromosomes where they are also underrelicated. Drosophila SNF2-related factor SUUR imparts locus-specific underreplication of polytene chromosomes. SUUR negatively regulates DNA replication fork progression; however, its mechanism of action remains obscure. Here we developed a novel method termed MS-Enabled Rapid protein Complex Identification (MERCI) to isolate a stable stoichiometric native complex SUMM4 that comprises SUUR and a chromatin boundary protein Mod(Mdg4)-67.2. Mod(Mdg4) stimulates SUUR ATPase activity and is required for a normal spatiotemporal distribution of SUUR in vivo. SUUR and Mod(Mdg4)-67.2 together mediate the activities of gypsy insulator that prevent certain enhancer-promoter interactions and establish euchromatin-heterochromatin barriers in the genome. Furthermore, SuUR or mod(mdg4) mutations reverse underreplication of intercalary heterochromatin. Thus, SUMM4 can impart late replication of intercalary heterochromatin by attenuating the progression of replication forks through euchromatin/heterochromatin boundaries. Our findings implicate a SNF2 family ATP-dependent motor protein SUUR in the insulator function, reveal that DNA replication can be delayed by a chromatin barrier and uncover a critical role for architectural proteins in replication control. They suggest a mechanism for the establishment of late replication that does not depend on an asynchronous firing of late replication origins.

Data availability

NGS data has been submitted to Gene Expression Omnibus (GEO, accession number GSE189421).

The following data sets were generated

Article and author information

Author details

  1. Evgeniya N Andreyeva

    Department of Cell Biology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    No competing interests declared.
  2. Alexander V Emelyanov

    Department of Cell Biology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    No competing interests declared.
  3. Markus Nevil

    University of North Carolina at Chapel Hill, Durham, United States
    Competing interests
    No competing interests declared.
  4. Lu Sun

    EpiCypher, Durham, United States
    Competing interests
    Lu Sun, Lu Sun is employed by Epicypher, Inc., a commercial developer and supplier of the EpiDyne® nucleosomes and associated remodeling assay platforms used in this study..
  5. Elena Vershilova

    Department of Cell Biology, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    No competing interests declared.
  6. Christina A Hill

    Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  7. Michael-C Keogh

    EpiCypher, Durham, United States
    Competing interests
    Michael-C Keogh, Michael C Keogh is employed by Epicypher, Inc., a commercial developer and supplier of the EpiDyne® nucleosomes and associated remodeling assay platforms used in this study..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2219-8623
  8. Robert J Duronio

    Integrative Program for Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  9. Arthur I Skoultchi

    Department of Cell Biology, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  10. Dmitry V Fyodorov

    Department of Cell Biology, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    dmitry.fyodorov@einsteinmed.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3080-1787

Funding

National Institutes of Health (R01 GM074233)

  • Dmitry V Fyodorov

National Institutes of Health (R01 GM129244)

  • Arthur I Skoultchi

National Institutes of Health (R01 GM124201)

  • Robert J Duronio

National Institutes of Health (R44 GM123869)

  • Michael-C Keogh

National Institutes of Health (T32 CA217824)

  • Markus Nevil

National Institutes of Health (K12 GM000678)

  • Markus Nevil

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Bruce Stillman, Cold Spring Harbor Laboratory, United States

Publication history

  1. Received: July 13, 2022
  2. Accepted: November 28, 2022
  3. Accepted Manuscript published: December 2, 2022 (version 1)

Copyright

© 2022, Andreyeva et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Evgeniya N Andreyeva
  2. Alexander V Emelyanov
  3. Markus Nevil
  4. Lu Sun
  5. Elena Vershilova
  6. Christina A Hill
  7. Michael-C Keogh
  8. Robert J Duronio
  9. Arthur I Skoultchi
  10. Dmitry V Fyodorov
(2022)
Drosophila SUMM4 complex couples insulator function and DNA replication control
eLife 11:e81828.
https://doi.org/10.7554/eLife.81828

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