September 19, 2005 | David F. Coppedge

Cell Has Automatic Jam-Clearing Proofreading Machinery

Findings at Rockefeller University have scientists excited.  DNA copying machines work on a “sliding clamp” that can hold two repair machines at the same time.  One is a low-fidelity repair tool, the other a high-fidelity repair tool.  Usually, the high-fidelity one is active, but when it needs a bigger hammer that is perhaps more effective but less accurate, it automatically switches to the other.  Here’s how the abstract of the paper in Molecular Cell by Indiani, O’Donnell et al.1 describes it in detail:

This report demonstrates that the beta sliding clamp of E. coli binds two different DNA polymerases at the same time.  One is the high-fidelity Pol III chromosomal replicase and the other is Pol IV, a low-fidelity lesion bypass Y family polymerase.  Further, polymerase switching on the primed template junction is regulated in a fashion that limits the action of the low-fidelity Pol IV.  Under conditions that cause Pol III to stall on DNA, Pol IV takes control of the primed template.  After the stall is relieved, Pol III rapidly regains control of the primed template junction from Pol IV and retains it while it is moving, becoming resistant to further Pol IV takeover events.  These polymerase dynamics within the beta toolbelt complex restrict the action of the error-prone Pol IV to only the area on DNA where it is required. (Emphasis added in all quotes.)

The paper says this is like having a “toolbelt” with different tools depending on the need of the project.  Bacteria have five DNA polymerase tools; humans have more.  Pol III is like the perfectionist editor that cuts out the typos, but it can stall.  Pol IV, like the plumber with a big wrench, isn’t as picayunish about the details but knows how to get the operation flowing again.  “The findings by O’Donnell and his colleagues,” the press release explains, “show that, because both polymerases are bound simultaneously to the beta clamp, it can pull either of the polymerases out if its toolbelt as needed.”  This apparently forms an automatic switchover mechanism where Pol III has priority.  A stall either loosens the grip of Pol III, or triggers a change in the sliding clamp that lets Pol IV intervene for the brute-force repair.
    A paper in Cell2 earlier this month described how multiple parts work together to fix mismatched DNA.  Since mismatched bases have serious health consequences, a suite of operations, still poorly understood, checks to detect and correct the error.  The paper by Zhang et al. describes part of the process:

Evidence is provided that efficient repair of a single mismatch requires multiple molecules of MutS-alpha-MutL-alpha complex.  These data suggest a model for human mismatch repair involving coordinated initiation and termination of mismatch-provoked excision.

The cover of the issue humorously highlights the problem with a picture of a guy with unmatched socks.  Mismatch in DNA is no joke, however; it can lead to cancer and genomic instability.

1Indiani et al., “A Sliding-Clamp Toolbelt Binds High- and Low-Fidelity DNA Polymerases Simultaneously,” Molecular Cell, Volume 19, Issue 6, 16 September 2005, pages 805-815.
2Zhang et al., “Reconstitution of 5′-Directed Human Mismatch Repair in a Purified System,” Cell, Volume 122, Issue 5, 9 September 2005, pages 693-705.

How could evolution ever devise a mechanism like an automatic toolbelt?  This is uncanny.  Here is a set of molecules that are programmed to act like a multi-faceted assembly line with a built-in, automatic-switching, multipart repair kit.  Neither the press release nor either paper made any attempt to explain how Tinker Bell and her mutation wand could have produced wonders like these.  Who would dare?

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Categories: Cell Biology, Genetics

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