**The Role of Telomeres and Telomere-associated Proteins as Components of Interactome in Cell-signaling Pathways**

Ekta Khattar and Vinay Tergaonkar

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/62130

#### **Abstract**

Telomeres represent ends of all eukaryotic chromosomes and serve specialized biological role in maintaining genomic integrity by preventing end fusions and degradation. Vari‐ ous protein complexes associate with telomeres to either protect them from DNA damage machinery or maintain telomere length homeostasis. These protein complex subunits cross talk with a variety of cell-signaling components to either maintain telomere integri‐ ty or perform other functions, which are either dependent or independent of telomeres and/or their telomeric role. Mutations in these protein components lead to the develop‐ ment of various human diseases, such as age-related disorders, which occur mainly due to telomere dysfunction or cancer development due to telomerase reactivation. This chap‐ ter focuses on the structural and functional aspects of telomeric proteins and their impor‐ tance in human diseases.

**Keywords:** Telomeres, shelterin, telomerase, TERT, telomere diseases, cancer

### **1. Introduction**

Human telomeres consist of TTAGGG tandem repeats, which are generally 3–15 kbp in length [1]. The distal end of telomere has a 3′ single-stranded overhang, which is also termed a Grich strand, and it forms a higher order structure (like a lariat) named t-loop [2]. In t-loop, both strands of the chromosome are joined to an earlier point in the double-stranded DNA by the 3′ strand end invading the strand pair to further form a D-loop. Formation of the D-loop completes the t-loop, thus establishing a capping structure, which protects chromosomes from degradation and recombination [3]. Figure 1A shows a schematic representation of telomere structure. The disruption of t-loop results in telomere dysfunction and induction of DNA

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

damage response (DDR) followed by cell cycle arrest [4]. Telomeres are bound by nucleosomes and a specialized complex known as shelterin, which is composed of six core protein subunits [5]. Shelterin determines the structure of telomeres. It is implicated in the formation of t-loops and also regulates the synthesis of telomeric DNA [6]. Additional proteins capable of inter‐ acting with shelterin proteins, such as DNA damage proteins, also play a role in maintaining telomere length and chromosomal stability [7].

**Figure 1.** Schematic representation of telomere end structure (A) and Telomere associated protein complexes (B).

Telomeres shorten with replication due to two major mechanisms: (A) end-replication problem and exonuclease-mediated resection in dividing cells, and (B) damage response to reactive oxygen species in nondividing cells [8].

DNA replication involves simultaneous duplication of antiparallel DNA strands, such that replication advances in opposite directions, across a leading strand and a lagging strand. On the leading strand, daughter strand synthesis takes place continuously in the 5′–3′ direction, whereas on the lagging strand template, DNA synthesis proceeds in the 5′–3′ direction discontinuously, leading to Okazaki fragments. The leading daughter strand is completely synthesized until DNA polymerase reaches 5′ end of the leading template. However, a primer is required for DNA replication to start. At the end of replication, RNA primer occupying the 5′ end of the daughter strand is removed, and it is not possible for the overlapping strand to be replicated. Due to this, the 5′ end of each antiparallel daughter strand becomes one primer length shorter. This is referred to as the end-replication problem, which results in chromosome shortening with each subsequent cell division. Theoretically, it should result in a loss of less than 10 bp with each replication cycle; however, the rate of loss is much higher and has been calculated to be 50–200 bp per division [9]. Exonuclease activity degrading the 5′ end is another major factor, which removes the RNA primer on the lagging strand and thus also leads to the formation of 3′-end overhang structure [10]. In vitro studies have also suggested the role of oxidative stress in telomere loss [11]. Correlative and experimental studies have also suggested links between oxidative damage and telomere loss in vivo [12]. Therefore, telomere length also serves as a biological clock and marker for chronological ageing. The solution to telomere shortening is the telomerase enzyme complex, which catalyzes de novo addition of TTAGGG repeats to chromosome ends, thus preventing telomere attrition [13].
