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ASAR lncRNAs control DNA replication timing through interactions with multiple hnRNP/RNA binding proteins.

Mathew Thayer1, Michael B Heskett2,3, Leslie G Smith1

  • 1Department of Chemical Physiology and Biochemistry,Oregon Health & Science University, Portland, United States.

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|June 19, 2024
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Summary

Very-long noncoding RNAs called ASARs are crucial for chromosome stability and replication timing. They act as scaffolds, assembling hnRNP complexes to maintain mammalian chromosome structure.

Keywords:
ASARRNA bindingReplicationXISTchromosomechromosomesgene expressiongeneticsgenomicshumanlong non-coding RNAmouse

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Area of Science:

  • Genetics
  • Molecular Biology
  • Epigenetics

Background:

  • Very-long noncoding RNAs (ASARs) are essential for controlling replication timing on human autosomes and maintaining chromosome stability.
  • ASARs are known to associate with their parent chromosomes.

Purpose of the Study:

  • To investigate the role of ASARs in genome-wide replication timing.
  • To identify RNA-binding proteins (RBPs) that interact with ASARs.
  • To elucidate the mechanism by which ASARs regulate replication timing and chromosome structure.

Main Methods:

  • Analysis of RNA-protein interaction data (ENCODE).
  • Genetic deletion and ectopic integration assays.
  • shRNA-mediated depletion of RBPs.
  • Assessing ASAR lncRNA localization and replication timing.

Main Results:

  • Numerous RBPs, particularly hnRNPs, interact with ASAR lncRNAs.
  • A specific domain within ASAR6-141 is rich in RBP interaction sites and controls replication timing in cis.
  • Depletion of specific hnRNPs causes ASARs to detach from chromosomes and disrupts synchronous replication, mimicking ASAR knockout effects.
  • ASARs play a role in the temporal order of genome-wide replication.

Conclusions:

  • ASARs function as critical RNA scaffolds for assembling hnRNP complexes.
  • These complexes are vital for maintaining the structural integrity of mammalian chromosomes.
  • ASARs are key regulators of replication timing and chromosome stability.