Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation

Abstract

Chromosome end protection is essential to protect genome integrity. Telomeres, tracts of repetitive DNA sequence and associated proteins located at the chromosomal terminus, serve to safeguard the ends from degradation and unwanted double strand break repair. Due to the essential nature of telomeres in protecting the genome, a number of unique proteins have evolved to ensure that telomere length and structure are preserved. The inability to properly maintain telomeres can lead to diseases such as dyskeratosis congenita, pulmonary fibrosis and cancer. In this review, we will discuss the known functions of mammalian telomere-associated proteins, their role in telomere replication and length regulation and how these processes relate to genome instability and human disease.

Fig. 1. Telomere Structure

(A) Telomeric DNA consists of repetitive DNA sequence, a duplex region and a ssDNA G-strand overhang (G-strand, red; C-strand blue). (B) The shelterin complex binds to both the duplex and ssDNA regions through specific protein-DNA interactions. (C) Formation of the t-loop involves strand invasion of the G-overhang to create a displacement-loop (D-loop). The t-loop is proposed to mask the chromosome end from DNA damage sensors. See text for further details.

Fig. 2. Telomere Replication

Telomere replication is a multi-step process which necessitates dynamic opening of the telomeric DNA. First, replication of the telomere duplex occurs via the conventional replication form machinery. Next nucleases cleave the C-strand to generate a G-overhang, which allows telomerase access to the G-strand terminus. The G-strands are then elongated by telomerase followed by C-strand fill-in synthesis, creating a short G-overhang. Finally the telomeres are re-bound by shelterin and the t-loop reforms. See text for further details.