• Cryo-EM reveals how '911' molecule helps

    From ScienceDaily@1:317/3 to All on Monday, March 21, 2022 22:30:46
    Cryo-EM reveals how '911' molecule helps fix damaged DNA

    Date:
    March 21, 2022
    Source:
    Van Andel Research Institute
    Summary:
    When something goes wrong during DNA replication, cells call their
    own version of 911 to pause the process and fix the problem --
    a failsafe that is critical to maintaining health and staving off
    disease. Now, scientists have for the first time revealed how a
    key piece of this repair process -- appropriately called the 911
    DNA checkpoint clamp -- is recruited to the site of DNA damage. The
    findings illuminate new insights into the way cells ensure genetic
    instructions are properly passed from one generation of cells to
    the next.



    FULL STORY ==========================================================================
    When something goes wrong during DNA replication, cells call their own
    version of 911 to pause the process and fix the problem -- a failsafe
    that is critical to maintaining health and staving off disease.


    ==========================================================================
    Now, scientists at Van Andel Institute and The Rockefeller University
    have for the first time revealed how a key piece of this repair process
    -- appropriately called the 911 DNA checkpoint clamp -- is recruited to
    the site of DNA damage.

    The findings, published today in Nature Structural and Molecular Biology,illuminate new insights into the way cells ensure genetic
    instructions are properly passed from one generation of cells to the
    next. The project was led by the study's co-corresponding authors Huilin
    Li, Ph.D., of VAI, and Michael E. O'Donnell, Ph.D., of The Rockefeller University and Howard Hughes Medical Institute.

    "DNA damage can have severe consequences, including cancer and other
    diseases.

    Because of this, our cells have a host of checks and balances to ensure
    DNA integrity," Li said. "Our high-resolution structure of the 911 DNA checkpoint clamp as it interacts with the molecule that loads it onto
    the DNA strand gives us a detailed look at the essential process of DNA
    repair. We hope these insights can be leveraged toward the development of
    new therapeutic strategies for diseases linked to DNA damage." Each day, billions of cells in the human body are replaced through cell division,
    a process by which one cell splits into two. This fundamental function
    drives growth and facilitates maintenance of tissues such as skin and
    muscle. A central part of this system is DNA replication, in which our
    genetic instruction manual is carefully replicated to ensure each cell
    has an accurate copy.

    DNA damage can result from mistakes in this process or through other
    factors that directly harm DNA, such as exposure to UV light from the
    sun or carcinogens such as tobacco smoke. When damage occurs, cells have emergency response systems to either stop replication until the problem
    can be repaired or to kill the cell, thus preventing the incorrect
    information from being passed on.

    This is where the 911 DNA checkpoint clamp comes in. When DNA damage is detected, the ring-shaped clamp is loaded on the DNA and transported
    to the site of the error. Once there, it sends a signal to halt cell
    division while also flagging other repair molecules to remove the damaged
    DNA and replace it with a corrected sequence.

    The structure was determined through use of VAI's cryo-electron
    microscopes (cryo-EM), which allow scientists to visualize molecular
    structures at the atomic level. In the case of the 911 DNA checkpoint
    clamp, cryo-EM also revealed a surprise: rather than loading onto DNA
    from the 3' (or "three prime") end like all other known DNA clamps, the
    911 clamp is loaded onto DNA from the opposite end, called the 5' ("five prime") end. This novel and unexpected finding reshapes what we know
    about DNA replication and sets the stage for further studies in this area.

    Other study authors are Fengwei Zheng, Ph.D., of VAI; and Roxana
    E. Georgescu, Ph.D., and Nina Y. Yao, Ph.D., of The Rockefeller
    University. Cryo-EM data were collected in collaboration with VAI's
    Cryo-EM Core and the David Van Andel Advanced Cryo-Electron Microscopy
    Suite.


    ========================================================================== Story Source: Materials provided by Van_Andel_Research_Institute. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Zheng, F., Georgescu, R.E., Yao, N.Y. et al. DNA is loaded through
    the 9-
    1-1 DNA checkpoint clamp in the opposite direction of the PCNA
    clamp. Nat Struct Mol Biol, 2022 DOI: 10.1038/s41594-022-00742-6 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220321132134.htm

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