August 14, 2007 | David F. Coppedge

DNA Repair Is Highly Coordinated

The remarkable ability of cells to repair DNA damage has been the subject of several recent articles.  As a long, physical molecule subject to perturbing forces, DNA is subject to breakage on occasion.  If repair mechanisms were not in place, the genetic information would quickly become hopelessly scrambled and life would break down.  Studies are revealing that multiple levels of control are involved in maintaining genomic integrity.

  1. Repair shop:  A study reported by Lawrence Berkeley Lab indicated that double-stranded break repairs tend to take place in specialized locations like “repair shops” in the nucleus.  They have “found evidence that indeed there are specific regions where broken DNA is concentrated for repair.”
  2. Damage suppressor:  Some sites in chromosomes are more subject to breakage than others.  A report from Tufts University reported by EurekAlert said that tumors can result from stalled replication at these sites.  Fortunately, there is a “tumor suppressor gene” whose presence is important for preventing tumor formation.  Most of the time, the article says, broken strands are repaired correctly.  Cancer can begin when the repair process goes awry, deleting or rearranging segments of DNA.
  3. Speed translator:  Researchers at Einstein School of Medicine found that RNA polymerase can translate up to 70 base pairs per second – much faster than has been previously reported.  The molecular machine stalls and pauses for unknown reasons along the strand, however, making the actual throughput less.  The researchers believe that the pauses are somehow involved in gene regulation.
  4. First response firefighters:  A study from Texas A&M University reported by EurekAlert found that two independent pathways converge on repair: chromatin remodeling and DNA checkpoint and repair.  “When molecular disaster strikes, causing structural damage to DNA, players in two important pathways talk to each other to help contain the wreckage,” the article began.  “….If DNA damage is like a fire that spreads when impaired cells divide and multiply, then the DNA checkpoint and repair system can be considered a first-response firebreak,” the article stated.  This stops cell division and allows the cell time to assess the damage.  Depending on the damage report, “The ‘fire’ is either doused by DNA repair or by programmed destruction of the cell.”
        The chromatin remodeling pathway, which shuffles DNA around nucleosomes to regulate access to DNA, is also involved, the report continued.  Modification of histones by the large “ATP-dependent chromatin remodeling complexes” serves to regulate the DNA checkpoint pathway.  The article mentioned that this pathway is conserved (i.e., unevolved) in all eukaryotes, from yeast to humans.
  5. Come again?  A sample of the complexity of DNA damage response can be found in the jargon of this paper from PNAS by Laura A. Lindsey-Boltz and Aziz Sancar at University of North Carolina School of Medicine, titled “Reconstitution of a human ATR-mediated checkpoint response to damaged DNA.”  If you have trouble following this, good thing your cells understand it: “We show that the damage sensor ATR in the presence of topoisomerase II binding protein 1 (TopBP1) mediator/adaptor protein phosphorylates the Chk1 signal-transducing kinase in a reaction that is strongly dependent on the presence of DNA containing bulky base lesions.  The dependence on damaged DNA requires DNA binding by TopBP1, and, indeed, TopBP1 shows preferential binding to damaged DNA.”  And that’s just the introduction.
  6. Stall at the typo:  Lindsey-Boltz and Sancar also suggested in a Commentary in PNAS that RNA Polymerase II, the DNA translator, could be “The most specific damage recognition protein in cellular responses to DNA damage.”  It acts like the “the universal high-specificity damage sensor for three major cellular responses to bulky DNA lesions,” they said.  When UV light has introduced an error, RNAP II stops and calls for help.  “The resulting structure recruits proteins that initiate repair, cell cycle checkpoints, or apoptosis [programmed cell death].”  Maybe this is what is going on when the translation process stalls: the word processing machine won’t proceed till the typo is fixed.
  7. Repair champ:  Raquel Sussman reported in PNAS on a model animal that is “endowed with special qualities for detecting external as well as internal abnormalities” and can “repair chromosomal lesions to a much greater extent than the human population.”  The animal is the zebrafish.  As an easy-to-study organism in the lab, it promises to help scientists gain insight into the causes of cancer and DNA damage, which can include ultraviolet rays and chemicals in the water.

The insights into DNA damage repair are part of a growing respect for the complexity of the cell.  A press release from U of Toronto reported by EurekAlert underscored this trend with its title, “Unravelling new complexity in the genome.”  It’s not just the number of protein-coding genes that are significant any more.  How the genes are switched on and off and regulated is becoming the focus of research.  Scientists used to view DNA as the master source of genetic information, but something is controlling DNA at higher levels.  “One outcome of these new studies is that the alternative splicing process appears to provide a largely separate layer of gene regulation that works in parallel with other important steps in gene regulation,” the article said.  The “regulatory code” now appears to be another level of genetic information above the genetic code.  It might be even more important than the information in the genes themselves.  Benjamin Blencowe (U of Toronto) remarked, “The number of genes and coordinated regulatory events involved in specifying cell and tissue type characteristics appear to be considerably more extensive than appreciated in previous studies.”

Isn’t the cell wonderful?  We each have trillions of them, but each one deserves our love and respect.  None of these articles, as usual, tried to explain how blind evolution could have produced all this coded information with its self-healing mechanisms.  Instead of Darwinizing it, maybe we should Pasteurize it: use the research to cure disease and improve the human condition, and to stand in awe of God.  Like Louis Pasteur said, “The more I study nature, the more I stand amazed at the work of the Creator.”

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