RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

Vannier, Jean‐Baptiste; Sandhu, Sumit; Petalcorin, Mark I.R.; Wu, Xiaoli; Nabi, Zinnatun; Ding, Hao; Boulton, Simon J.

doi:10.1126/science.1241779

Cited by 199 publications

(221 citation statements)

References 26 publications

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“…It also implies that Rad51 activity in mESCs is not restricted to the restart of collapsed replication forks [25]; rather, it might extend to the repair of replication defects. Because HR activity in mESCs is not related to replication fork progression, the replication speed in mESCs is similar to that in MEFs [45]. The localization of Rad51 within 100-600 nm of ORC2 indicates that the majority of Rad51 foci formed near the replication origin.…”

Section: Discussionmentioning

confidence: 78%

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

Yoon

Kim

et al. 2014

Stem Cells and Development

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Homologous recombination (HR) maintains genomic integrity against DNA replication stress and deleterious lesions, such as double-strand breaks (DSBs). Rad51 recombinase is critical for HR events that mediate the exchange of genetic information between parental chromosomes in eukaryotes. Additionally, Rad51 and HR accessory factors may facilitate replication fork progression by preventing replication fork collapse and repair DSBs that spontaneously arise during the normal cell cycle. In this study, we demonstrated a novel role for Rad51 during the cell cycle in mouse embryonic stem cells (mESCs). In mESCs, Rad51 was constitutively expressed throughout the cell cycle, and the formation of Rad51 foci increased as the cells entered S phase. Suppression of Rad51 expression caused cells to accumulate at G2/M phase and activated the DNA damage checkpoint, but it did not affect the self-renewal or differentiation capacity of mESCs. Even though Rad51 suppression significantly inhibited the proliferation rate of mESCs, Rad51 suppression did not affect the replication fork progression and speed, indicating that Rad51 repaired DNA damage and promoted DNA replication in S phase through an independent mechanism. In conclusion, Rad51 may contribute to G2/M transition in mESCs, while preserving genomic integrity in global organization of DNA replication fork.

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Section: Discussionmentioning

confidence: 78%

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

Yoon

Kim

et al. 2014

Stem Cells and Development

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“…RTEL1 is a candidate for this function, as RTEL1 and BLM repress fragile telomeres in an additive manner that is on a par with the repression by TRF1 (Sfeir et al 2009;Vannier et al 2012). RTEL1 contains a proliferating cell nuclear antigen (PCNA)-interacting motif (Ding et al 2004) that is required for the repression of the fragile telomere phenotype (Vannier et al 2013). How TRF1 interacts with PCNA-bound RTEL1 to manage telomere replication merits further investigation, as do the roles of Timeless and Topoisomerase IIa (Leman et al 2012;d'Alcontres et al 2014).…”

Section: The Role Of Blm At Telomeresmentioning

confidence: 99%

TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling

et al. 2014

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The semiconservative replication of telomeres is facilitated by the shelterin component TRF1. Without TRF1, replication forks stall in the telomeric repeats, leading to ATR kinase signaling upon S-phase progression, fragile metaphase telomeres that resemble the common fragile sites (CFSs), and the association of sister telomeres. In contrast, TRF1 does not contribute significantly to the end protection functions of shelterin. We addressed the mechanism of TRF1 action using mouse conditional knockouts of BLM, TRF1, TPP1, and Rap1 in combination with expression of TRF1 and TIN2 mutants. The data establish that TRF1 binds BLM to facilitate lagging but not leading strand telomeric DNA synthesis. As the template for lagging strand telomeric DNA synthesis is the TTAGGG repeat strand, TRF1-bound BLM is likely required to remove secondary structures formed by these sequences. In addition, the data establish that TRF1 deploys TIN2 and the TPP1/POT1 heterodimers in shelterin to prevent ATR during telomere replication and repress the accompanying sister telomere associations. Thus, TRF1 uses two distinct mechanisms to promote replication of telomeric DNA and circumvent the consequences of replication stress. These data are relevant to the expression of CFSs and provide insights into TIN2, which is compromised in dyskeratosis congenita (DC) and related disorders.

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“…TRF2 is essential for forming the t-loop structure (Griffith et al, 1999;Stansel et al, 2001;Doksani et al, 2013). In S phase, TRF2 recruits Werner syndrome helicase (WRN) and RTEL1 to unwind t-loops for replication fork progression and telomere elongation by telomerase (Opresko et al, 2004;Barber et al, 2008;Vannier et al, 2012Vannier et al, , 2013Sarek et al, 2015;reviewed by Blackburn, 2001;Palm and de Lange, 2008). Disruption of RTEL1 results in SLX4-mediated t-loop excision and formation of extrachromosomal telomeric repeats (ECTRs) and telomere shortening (Vannier et al, 2012) (see below).…”

Section: The Response To Dysfunctional Telomeresmentioning

confidence: 99%

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

Muraki

Murnane

2017

Genes Genet. Syst.

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In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini. Telomeres and subtelomeric regions are poor substrates for DNA replication; therefore, regions near telomeres are prone to replication fork stalling and chromosome breakage. Moreover, DSBs near telomeres are poorly repaired. As a result, when DSBs occur near telomeres in normal cells, the cells stop proliferating, while in cancer cells, subtelomeric DSBs induce rearrangements due to the absence of cell cycle checkpoints. The sensitivity of subtelomeric regions to DSBs is due to the improper regulation of processing, because although C-NHEJ is functional at subtelomeric DSBs, excessive processing results in an increased frequency of large deletions and chromosome rearrangements involving A-NHEJ.

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RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication

Cited by 199 publications

References 26 publications

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

Rad51 Regulates Cell Cycle Progression by Preserving G2/M Transition in Mouse Embryonic Stem Cells

TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling

The DNA damage response at dysfunctional telomeres, and at interstitial and subtelomeric DNA double-strand breaks

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