The role of double-strand break repair pathways at functional and dysfunctional telomeres

Abstract

Telomeres have evolved to protect the ends of linear chromosomes from the myriad of threats posed by the cellular DNA damage signaling and repair pathways. Mammalian telomeres have to block nonhomologous end joining (NHEJ), thus preventing chromosome fusions; they need to control homologous recombination (HR), which could change telomere lengths; they have to avoid activating the ATM (ataxia telangiectasia mutated) and ATR (ATM- and RAD3-related) kinase pathways, which could induce cell cycle arrest; and they have to protect chromosome ends from hyperresection. Recent studies of telomeres have provided insights into the mechanisms of NHEJ and HR, how these double-strand break (DSB) repair pathways can be thwarted, and how telomeres have co-opted DNA repair factors to help in the protection of chromosome ends. These aspects of telomere biology are reviewed here with particular emphasis on recombination, the main focus of this collection.

Figure 1.

Telomeres, shelterin, and the end-protection problem. (A) The structure of mammalian telomeres, including the telomeric double-stranded DNA, the telomeric 3′ overhang, and the shelterin complex. (B) Schematic of the interactions among the six subunits that make up shelterin, their interactions with DNA, and their combined repression of the pathways that threaten telomeres (the end-protection problem).

Figure 2.

Generation of the telomeric 3′ overhang. Schematic of the three steps involved in the regeneration of the 3′ overhang at the telomere replicated by leading- and lagging-strand DNA synthesis. See text for details. (Figure based on data from Wu et al. 2012.)

Figure 3.

Repression of hyperresection at telomeres. ATM/CtIP-dependent resection at telomeres is repressed by several independent pathways. On the one hand, the 53BP1 binding partner RIF1 inhibits resection at telomeres that have become dysfunctional such that the ATM kinase pathway has been activated. On the other hand, resection is repressed by TRF2 in shelterin preventing the activation of the ATM kinase and protecting telomeres from moderate resection when 53BP1 is absent (top left and right). In addition, other components in shelterin repress resection so that extensive hyperresection only occurs in the absence of the complete shelterin complex (bottom right).

Figure 4.

Homologous recombination (HR)-related structures invoked at telomeres. (A) The structure of the T-loop compared to the strand invasion step in HR (telomeric sequences written from 5′ to 3′). (B) Possible structures at the base of the T-loop compatible with T-loop detection after psoralen cross-linking. (C) Products predicted from the indicated Holliday junction (HJ) resolution (cleavage and ligation) of the two T-loop structures shown. The products of the double Holliday junction (dHJ) schematic have been detected in cells overexpressing a mutant form of TRF2 lacking the amino-terminal basic domain (Wang et al. 2004). (D) Proposed mechanisms of telomere DNA synthesis in ALT cells. See text for discussion.