Drosophila SUMM4 complex couples insulator function and DNA replication control
- Albert Einstein College of Medicine, United States
- University of North Carolina at Chapel Hill, United States
- 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).
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SUMM4 complex couples insulator function and DNA replication timing controlNCBI Gene Expression Omnibus, GSE189421.
Article and author information
Author details
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
- Bruce Stillman, Cold Spring Harbor Laboratory, United States
Publication history
- Received: July 13, 2022
- Accepted: November 28, 2022
- 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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Drosophila SUMM4 complex couples insulator function and DNA replication control
eLife 11:e81828.
https://doi.org/10.7554/eLife.81828
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