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Related Concept Videos

Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

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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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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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Homologous Recombination02:31

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The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
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Translesion DNA Polymerases02:10

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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
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DNA replication is carried out by a large complex of proteins that act in a coordinated matter to achieve high-fidelity DNA replication. Together this complex is known as the DNA replication machinery or the replisome.
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In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
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Hierarchical Coordination of Polymerase Theta and RAD51 Resolves Clustered Replication Fork Collapse.

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    Polymerase theta (Polθ)-mediated end joining (TMEJ) repairs DNA double-strand breaks in healthy cells. TMEJ resolves complex DNA damage when homologous recombination (HR) is insufficient, safeguarding genome stability.

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    Area of Science:

    • Molecular Biology
    • Genetics
    • DNA Repair Mechanisms

    Background:

    • Polymerase theta (Polθ)-mediated end joining (TMEJ) is an alternative DNA double-strand break repair pathway.
    • TMEJ has been primarily studied in homologous recombination (HR)-deficient cells.
    • The role of TMEJ in HR-proficient cells remains largely unexplored.

    Purpose of the Study:

    • To investigate the role of TMEJ in DNA repair in HR-proficient mammalian cells.
    • To elucidate the mechanism of Polθ recruitment and its function in resolving interstrand crosslinks (ICLs).

    Main Methods:

    • Recruitment of Polθ downstream of canonical ICL repair steps.
    • Interaction of Polθ with ubiquitylated RAD51 filaments at sites of unresolved HR.
    • Genomic scar profiling and targeted ICL repair assays to analyze TMEJ function.

    Main Results:

    • TMEJ repairs a subset of ICLs refractory to HR, particularly clustered ICLs causing replication fork collapse.
    • Polθ recruitment is dependent on RAD51 ubiquitylation.
    • TMEJ acts as a backup repair pathway when HR is insufficient.

    Conclusions:

    • TMEJ plays an indispensable role in repairing ICLs in HR-proficient mammalian cells.
    • A RAD51 ubiquitylation-dependent mechanism facilitates Polθ recruitment for TMEJ.
    • TMEJ is a hierarchically deployed pathway crucial for maintaining genome stability against replication-associated DNA damage.