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An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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Before a cell can divide, it must accurately replicate all of its chromosomes, including the DNA and its associated histone and non-histone proteins.  This process begins at numerous origins of replication during the S phase of the cell cycle in each of a cell’s chromosomes simultaneously. Certain nucleotides can act as origins of replication, but these sequences are not well defined - especially in complex, multi-cellular, eukaryotic species. The length of DNA that spans an origin...
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Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...
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Deep learning meets histones at the replication fork.

Hiten D Madhani1

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

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|September 6, 2024
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Summary
This summary is machine-generated.

Parental histone transfer during DNA replication is crucial for epigenetic inheritance. A replisome component, Mrc1/CLASPIN, acts as a histone chaperone, facilitating this essential parental histone transfer to daughter DNA strands.

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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Chromatin Biology

Background:

  • Epigenetic inheritance relies on passing chromatin states across cell divisions.
  • Parental histone proteins (H3-H4 tetramers) must be distributed to both new DNA strands during replication.
  • The precise mechanisms ensuring equitable histone distribution remain incompletely understood.

Purpose of the Study:

  • To identify factors mediating the transfer of parental H3-H4 tetramers to daughter DNA duplexes.
  • To elucidate the role of replication machinery components in epigenetic inheritance.

Main Methods:

  • Utilized yeast genetics and inheritance assays to study histone segregation.
  • Employed AlphaFold2-multimer predictions for structural insights.
  • Integrated biochemical approaches to validate protein functions.

Main Results:

  • Identified Mrc1 (also known as CLASPIN) as a critical component of the DNA replisome.
  • Demonstrated that Mrc1 functions as a chaperone for H3-H4 tetramers.
  • Showed Mrc1's essential role in the transfer of parental H3-H4 tetramers to both daughter DNA strands during replication.

Conclusions:

  • Mrc1/CLASPIN is a key histone chaperone involved in epigenetic inheritance.
  • The DNA replication machinery directly participates in ensuring the faithful transmission of epigenetic information.
  • This finding provides a mechanistic link between DNA replication and the maintenance of chromatin states.