Summary

Within the cell, DNA is organized into large structures called chromosomes. Although the DNA forms the foundations for each chromosome, as much as half of each chromosome is composed of protein. Chromosomes can bo either Circular or linear; however, each Cell has a characteristic number and composition of chromosomes. We now know the sequence of the entire genome of numerous organisms. These sequences have revealed that the underlying DNA of each organism's chromosomes is used more or less efficiently to encode proteins. Simple organisms tend to use the majority of DNA to encode protein; however, more complex organisms use only a small portion of their DNA In actually encode proteins or RNAs.

Cells must carefully maintain their complement of chromosomes as they divide. Each chromosome must have DNA elements that direct chromosome maintenance during ceil division. All chromosomes must have one or more origins of replication. In oukaryatic cells, centromeres play a critical role in the segregation of chromosomes and telomeres help to protect and replicate ihe ends of linear chromosomes. Eukaryotic cells carefully separate the events thai duplicate and segregate chromosomes as cell division proceeds. Chromosome segregation can occur in one of (wo manners. During mitosis, a highly specialized apparatus ensures that one copy of each duplicated chromosome is delivered to each daughter cell. During ifieio-sis, art additional round of chromosome segregation {without UNA replication) further reduces the number of chromosomes in the resulting daughter cells.

The combination of eukaryotic DNA and its associated proteins is referred to as chromatin. The fundamental unit of chromatin is the nucleosome, which is made up of two copies each of the com hi stones (H2A, H2B. H3, and H4) and approximately 147 bp of DNA. This protein-DNA complex serves two important functions in the cell: it compacts the DNA to allow il to fit into the nucleus and it restricts the accessibility of the DNA. This latter function is extensively exploited by the cell to regulate many different DNA transactions including gene expression.

The atomic structure of the nucleosome shows that the DNA is wrapped about 1.7 limes around the outside of a disc-shaped, hislone protein core. The interactions between the DNA and the histones are extensive but uniformly base nonspecific. The nature of these interactions explain both the bending of the DNA around the histone

Octal tier and Ihe ability of virtually all DNA sequences to be incorporated into a nucleosome. This structure also reveals the location of the N-lerminal tails of the histones and their role in directing the path of the DNA around the histones.

Once DNA is packaged into nucleosomes, it has the ability to form more complex structures that allow additional compaction of the DNA. This process is facilitated by a fifth hisloniî called Hi. By binding the DNA associated with the nucleosome, HI causes the DNA to wrap motft tightly around the octamer. A more compact form of chromatin, the 3Q-nm fiber, is readily formed by arrays of Hi-hound nucleosomes. This structure is more repressive than DNA packaged into nucleosomes alone. Current evidence suggests that the incorporation of DNA into this structure results in a dramatic reduction in its accessibility to the enzymes and proteins involved in transcription of the DNA.

The interaction of the DNA with the histones in the nucleosome is dynamic, allowing DNA-binding proteins intermittent access to the DNA. Nueleosome-remodeling complexes increase tho accessibility of DNA incorporated into nucleosomes by increasing the mobility of .nucleosomes. Three forms of mobility can be observed: sliding of ihe histone octamer along the DNA, complete transfer of the histone octamer from one DNA molecule to another, and more subtle remodeling of the protein-DNA interactions within the nucleosomes. These complexes are localized to particular regions of the genome to facilitate alterations in chromatin accessibility. A subset of nucleosomes is restricted to fixed positions in the genome and ore said to be "positioned." Nucleosome positioning can he directed by DNA-binding proteins or particular DNA sequences.

Modification of the histone N-terminal latls also alters the accessibility of chromatin. The types of modifications include acetyl alien and melhyiation of lysines and phosphorylation of serines. Acetylation of N-teïminal tails is frequently associated with regions of active gene expression. These modifications alter both the properties of Ihe nucleosome itself as well as acting as binding sites for proteins that influence the accessibility of the chromatin. These modifications also recruit enzymes that perform the same modification, leading to similar modification of adjacent nucleosomes. It is likely that this leads to the stable propagation of regions of modified nucleosomes/chromatin as the chromosomes are duplicated.

Nucleosomes are assembled immediately after the DNA is replicated, leaving little time during which the DNA is unpackaged. This involves the function of specialized histone chaperones that escort the II3-1I4 tetramers and H2A-H2B dimers to the replication fork. During the replication of the DNA, nucleosomes are tran siently disassembled. Histone H3-H4 tetramers and H2A-H2B dimers are randomly distributed to one or the other daughter molecules. On average, each new DNA molecule receives half old and half new histones. Thus, both chromosomes inherit modified histones which can then act as "seeds" for the similar modification of adjacent histones.

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