RTEL1: an essential helicase for telomere maintenance and the regulation of homologous recombination

Abstract

Telomere maintenance and DNA repair are crucial processes that protect the genome against instability. RTEL1, an essential iron-sulfur cluster-containing helicase, is a dominant factor that controls telomere length in mice and is required for telomere integrity. In addition, RTEL1 promotes synthesis-dependent strand annealing to direct DNA double-strand breaks into non-crossover outcomes during mitotic repair and in meiosis. Here, we review the role of RTEL1 in telomere maintenance and homologous recombination and discuss models linking RTEL1's enzymatic activity to its function in telomere maintenance and DNA repair.

Figure 1.

Model for RTEL1 promoting synthesis-dependent strand annealing (SDSA). (a) After a DSB is sensed, the two duplex ends are resected to give 3′-ssDNA that is subsequently bound by RPA (orange). RPA is replaced by RAD51 recombinase (blue) to form a nucleoprotein filament that searches and invades the homologous dsDNA, forming a D-loop. The invaded strand serves as a primer for DNA synthesis, which copies the information on the homologous DNA strand. RTEL1 (green) promotes SDSA by the displacement of a 3′-end invaded D-loop. Although the mechanism by which RTEL1 promotes strand displacement is unknown, RTEL1 is proposed to recognize the ssDNA–dsDNA junction via its FeS domain, and act as a 5′- to 3′-helicase. The displaced strand can now anneal to the other processed DNA end and the repair reaction will be completed by DNA synthesis and ligation, resulting in a non-crossover outcome. Note that RTEL1 may displace invading strands from both of the processed DNA ends, however, only one invading strand is shown for clarity. Alternative models of RTEL1 action include: (b) RTEL1 translocation in a 5′- to 3′-direction along template strand, as opposed to the invading strand. (c) Although it is thought that SDSA occurs earlier than double Holliday junction formation, it is also possible, though less likely, that RTEL1 may act on the other processed DNA end. This activity might prevent the other processed DNA end from becoming part of the repair reaction, known as second end capture, and so prevent the formation of a double Holliday junction, which could be resolved as a crossover product.

Figure 2.

Model for RTEL1 anti-recombinase function in telomere maintenance. (a) A telomere end is protected from being recognized as a DSB by folding back onto itself in a structure known as the T-loop. At the base of the T-loop, the naturally occurring 3′-ssDNA overhang invades the double-stranded repetitive telomere DNA forming a D-loop. The similarity of D-loop intermediates during DNA repair and telomere maintenance have led to the proposal that RTEL1 (green) may reverse T-loops. (b) D-loops can also form at telomeres by invasion of the 3′-ssDNA telomere overhang into sister or non-sister telomeres, leading to telomere strand-exchange and chromosome entanglements. RTEL1 may reverse inappropriate T-loop formation and thereby prevent telomere strand exchange.