July 28, 2004 | David F. Coppedge

Spaghetti in a Basketball: How the Cell Packs DNA for Controlled Access

The beginning sentence of an article in Current Biology1 can’t help but grab your attention:

Imagine trying to stuff about 10,000 miles of spaghetti inside a basketball.  Then, if that was not difficult enough, attempt to find a unique one inch segment of pasta from the middle of this mess, or try to duplicate, untangle and separate individual strings to opposite ends.  This simple analogy illustrates some of the daunting tasks associated with the transcription, repair and replication of the nearly 2 meters of DNA that is packaged into the confines of a tiny eukaryotic nucleus.  The solution to each of these problems lies in the assembly of the eukaryotic genome into chromatin, a structural polymer that not only solves the basic packaging problem, but also provides a dynamic platform that controls all DNA-mediated processes within the nucleus.

The article by Craig L. Peterson and Marc-André Laniel is otherwise boringly titled “Histones and histone modifications,” but after this appetizing start, goes into detail about how the tangled mess of alphabetized pasta is exquisitely controlled, folded, unfolded and copied continuously inside the cell, with the help of numerous protein and RNA parts.
    Of special importance are the histone proteins that comprise chromatin.  Scientists have been discovering for several years now that these histones have “tails” of amino acids that can be altered through numerous ways.  These alterations, called “post-translational modifications,” seem to influence the DNA wrapped around them in many important ways.  They signal genes to activate for transcription, places needing DNA repair, places to start or repress DNA elongation or replication, where to silence telomeres, places to deposit more chromatin, and more.  A table in the article lists 95 histone modifications and their functions that are known so far.  Some are involved in mitosis (cell division), spermatogenesis, X-chromosome inactivation (silencing one of the two X-chromosomes in the female), apoptosis (programmed cell death), DNA “memory” and other important cell processes.  Some have said these modifications constitute a “histone code” (see “Cell memory borders on the miraculous,” 11/04/2002 headline).  These authors term it differently, but no less amazing: “rather than a histone code there are instead clear patterns of histone marks that can be differentially interpreted by cellular factors, depending on the gene being studied and the cellular context.”  Activities like DNA repair or replication are often accompanied by histone modifications, for instance, as if one enzyme leaves its mark on a histone to signal a follow-up function.  Complexes of small RNAs and enzymes depend on these markers to know where to go and what to do; the histone tails serve as attachment points for specific enzymes.  And if that is were not amazing enough, the interplay of neighboring histone markers, or cross-talk, can have “a profound effect on enzyme activity.”   The authors explain, “Thus, in many ways histone tails can be viewed as complex protein-protein interaction surfaces that are regulated by numerous post-translational modifications.  Furthermore, it is clear that the overall constellation of proteins bound to each tail plays a primary role in dictating the biological functions of that chromatin domain.”  Finally, since some of these histone states can survive cell division, they augment what’s inherited beyond DNA alone.  The authors provide no suggestions on how this system might have evolved.
    On a related subject, three geneticists from Scotland describe, in the same issue of Current Biology,2 how DNA packs itself so tightly and efficiently.  There are specialized proteins called condensins that perform this job.  They are members of a set of hairpin-shaped enzymes called “structural maintenance of chromosomes” enzymes (SMCs, see 08/07/2002 headline).  The authors remind us that “These extraordinary molecules are conserved [i.e., unevolved] from bacteria to humans.”  Scientists are beginning to be able to watch condensin do its amazing work in real time (see “DNA folds with molecular velcro,” 06/07/2004 headline).  Condensin produces “supercoils” of DNA, one of many steps in packing the delicate DNA strands into a hierarchy of coils that results in a densely-packed chromosome.  “It is not entirely clear how the DNA is held in this supercoiled state,” they say, “but several studies suggest that the V-shaped arms of the condensin complex may loop and clamp the DNA in place.”  This clamping is “rapid and reversible.”  Scientists watching the process in both bacteria and humans are “showing that both vertebrate and bacterial condensins drive DNA compaction in an ATP-dependent fashion with a surprising level of co-operativity that was not fully appreciated.”  The condensin molecules work as a team; if not enough condensin is around, nothing happens.
    These authors point out also that condensin is just one of many enzymes involved in chromosome formation.  Think about how remarkable it is that during each cell division, the chromosomes are structured so reliably that they can be labeled and numbered under the microscope.  “Our own proteomic analysis,” they claim, “has identified over 350 chromosome-associated proteins, so there is clearly more work to be done.”  There is no mention of evolution in this article, either.

1Peterson and Laniel, “Histones and Histone Modifications,” Current Biology, Volume 14, Issue 14, 27 July 2004, Pages R546-R551, doi:10.1016/j.cub.2004.07.007.
2Porter, Khoudoli and Swedlow, “Chromosome Condensation: DNA Compaction in Real Time,” Current Biology, Volume 14, Issue 14, 27 July 2004, Pages R554-R556, doi:10.1016/j.cub.2004.07.009.

The views we are getting of a cell since the invention of the microscope can be likened to those from a UFO descending from earth orbit to ground level.  From orbit, a city like Boston seems to have a lot of structure and organization.  As we descend into this alien world, more and more organization becomes apparent, till from airline height, we see complex transportation arteries and machinery apparently all coordinated and purposeful.  From helicopter height, individual workers begin to come into focus.  We are now approaching ground level, and able to watch factory workers and figure out what it is they are doing.  Just imagine what Leeuwenhoek would think, considering he only got the orbital view.
    It’s not getting any easier for the Darwin Party.  If the mental picture of 10,000 miles of spaghetti in a basketball didn’t grab you, considering it is efficiently packaged with each inch of pasta accessible and reproducible, then maybe you just hate Italian food or sports and need a more suitable analogy.  Breathes there a man with soul so dead who never to himself hath said, This is my own, my Creator’s hand?  Yes, sadly, there is; read next headline.

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