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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