Telomere DNA sequences are recognized by sequence-specific DNA-binding proteins that attract an enzyme, called telomerase, that replenishes these sequences each time a cell divides. Telomerase recognizes the tip of an existing telomere DNA repeat sequence and elongates it in the 5ʹ-to-3ʹ direction, using an RNA template that is a component of the enzyme itself to synthesize new copies of the repeat (Figure 5–33). The enzymatic portion of telomerase resembles other reverse transcriptases, proteins that synthesize DNA using an RNA template, although, in this case, the telomerase RNA also contributes functional groups to make the catalysis more efficient. After extension of the parental DNA strand by telomerase, replication of the lagging strand at the chromosome end can be completed by the conventional DNA polymerases, using these extensions as a template to synthesize the complementary strand (Figure 5–34).
Figure 5–32 Formation of nucleosomes behind a replication fork. Parental  H3-H4 tetramers are distributed at random  to the daughter DNA molecules, with roughly equal numbers inherited by each daughter. In contrast, H2A-H2B dimers  are released from the DNA as the replication fork passes. This release begins just in front of the replication fork and is facilitated by chromatin remodeling complexes that move with the fork. Histone chaperones (NAP1 and  CAF1) restore the full complement of histones to daughter molecules using both parental and newly synthesized histones. Although some daughter nucleosomes contain only parental histones or only newly synthesized histones, most are hybrids of old and new. For simplicity, the DNA double helix shown as a single red line. (Adapted from J.D. Watson et al., Molecular Biology of the Gene, 5th ed. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2004.) remainder of telomerase proteintelomerase RNA region of telomerase RNA used as template “palm“—active site of telomerase protein rest of synthesized chromosome telomere DNA
Telomeres Are Packaged Into Specialized Structures That Protect the Ends of Chromosomes
The ends of chromosomes present cells with an additional problem. As we will see in the next part of this chapter, when a chromosome is accidently broken, the break is rapidly repaired (see Figure 5–45). Telomeres must clearly be distinguished from these accidental breaks; otherwise the cell will attempt to “repair” telomeres, causing chromosome fusions and other genetic abnormalities. Telomeres have several features to prevent this from happening.
A specialized nuclease chews back the 5ʹend of a telomere leaving a protruding single-strand end. This protruding end—in combination with the GGGTTA repeats in telomeres—attracts a group of proteins that form a protective chromosome cap known as shelterin. In particular, shelterin “hides” telomeres from the cell’s damage detectors that continually monitor DNA. When human telomeres are artificially cross-linked and viewed by electron microscopy, structures known as “t-loops” are observed in which the protruding end of the telomere loops back and tucks itself into the duplex DNA of the telomere repeat sequence (Figure 5–35). It is believed that t-loops are regulated by shelterin and provide additional protection for the ends of chromosomes.
incomplete, newly synthesized lagging strand direction of AACCCC telomere 5˜ synthesisTELOMERASE EXTENDS 3˜ END telomerase with bound RNA template