BLM helicase facilitates telomere replication during leading strand synthesis of telomeres

Drosopoulos, William C.; Kosiyatrakul, Settapong T.; Schildkraut, Carl L.

doi:10.1083/jcb.201410061

Cited by 133 publications

(123 citation statements)

References 60 publications

(116 reference statements)

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“…Intriguingly, Stavropoulos and colleagues showed that, in ALT cells, BLM interacts with TRF2 and that overexpression of BLM in ALT cells increases telomeric DNA, suggesting that BLM may play an important role in ALT telomere synthesis (79). The proposed functions of BLM at the telomere include suppressing the fragile-telomere phenotype (16), processing the late-replicating intermediate structure (78), and aiding fork progression possibly through unfolding the G4s (80,81). Here we show that, similar to its role during DSB repair (70), BLM is also required for DNA end resection and HR in our MR-SAT system.…”

Section: Discussionmentioning

confidence: 99%

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

Pan

Drosopoulos

Sethi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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113

126

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In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.aithfully replicating its genome is vital for the fitness and health of a mammalian cell. The replisome frequently encounters a variety of impediments throughout the genome. The temporary/transient slowing or stalling of the replication fork is referred to as replication stress (1, 2). The list of endogenous sources of replication stress is still growing. Nonetheless, the wellrecognized sources of replication stress include unrepaired DNA lesions, mis-incorporated ribonucleotides, unique DNA sequences that are prone to form secondary structures (e.g., G-quadruplex or G4), collision of the replication fork with the transcriptional machinery, an RNA-DNA hybrid (or R-loop) that is formed between a nascent RNA and the adjacent displaced single-stranded DNA (ssDNA), common fragile sites (CFS), and tightly packed genomic regions, such as heterochromatin (2). Because of these constant challenges faced by the replisome, mammalian cells have developed elaborate and complex strategies to resolve the replication stress and ensure the successful completion of DNA replication (1-4).One of the endogenous loci/regions that frequently pose challenges to the replisome is the telomere. Mammalian telomeres are tandem repetitive DNA sequences [the large majority as (TTAGGG) n ] located at the end of every linear chromosome. The addition of TTAGGG is catalyzed by an enzyme called telomerase, a large ribonucleoprotein complex with reverse tr...

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Section: Discussionmentioning

confidence: 99%

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

Pan

Drosopoulos

Sethi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

113

126

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“…BLM also resolves late replication intermediates and prevents the formation of ultrafine anaphase bridges (UBFs) at telomeres and common fragile sites (CFSs) (26,29). More recently, BLM has been shown to stimulate polymerization across telomeric G-rich sequences that are replicated by leading-strand synthesis from origin firing within the telomere (27). In spite of the functional overlaps, our study reveals a significant difference between WRN and BLM in coordinating cleavage of the upstream fragment during strand displacement.…”

Section: Discussionmentioning

confidence: 57%

The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

Reddy

Comai

2017

Molecular and Cellular Biology

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The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulates DNA polymerase ␦ progression across telomeric G-rich repeats, only WRN promotes sequential strand displacement synthesis and FEN1 cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity, as well as the conserved winged-helix (WH) motif and the helicase and RNase D C-terminal (HRDC) domain play important but distinct roles in this process. Remarkably, WRN also influences the formation of FEN1 cleavage products during strand displacement on a nontelomeric substrate, suggesting that WRN recruitment and cooperative interaction with FEN1 during lagging-strand synthesis may serve to regulate sequential strand displacement and flap cleavage at other genomic sites. These findings define a biochemical context for the physiological role of WRN in maintaining genetic stability.

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“…Interfering with the integrity of the shelterin complex via changing the levels of TRF1 or TRF2 also induces telomere fragility (Martinez et al 2009;Sfeir et al 2009) and gives rise to T-UFBs (d 'Alcontres et al 2014;Nera et al 2015). TRF1 was shown to protect against fragility by recruiting BLM to the telomeres (Sfeir et al 2009), suggesting that BLM facilitates replication (Drosopoulos et al 2015) or disentangles late-replicating structures at these regions Barefield and Karlseder 2012). In contrast to CFS-UFBs, inhibition of TopIIα by ICRF-193 induces T-UFBs, and TRF1 has been shown to recruit TopIIα to telomeres.…”

Section: Ufbs At Telomeresmentioning

confidence: 99%

Knotty Problems during Mitosis: Mechanistic Insight into the Processing of Ultrafine DNA Bridges in Anaphase

Sarlós

Biebricher

Petermann

et al. 2017

Cold Spring Harb Symp Quant Biol

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To survive and proliferate, cells have to faithfully segregate their newly replicated genomic DNA to the two daughter cells. However, the sister chromatids of mitotic chromosomes are frequently interlinked by so-called ultrafine DNA bridges (UFBs) that are visible in the anaphase of mitosis. UFBs can only be detected by the proteins bound to them and not by staining with conventional DNA dyes. These DNA bridges are presumed to represent entangled sister chromatids and hence pose a threat to faithful segregation. A failure to accurately unlink UFB DNA results in chromosome segregation errors and binucleation. This, in turn, compromises genome integrity, which is a hallmark of cancer. UFBs are actively removed during anaphase, and most known UFB-associated proteins are enzymes involved in DNA repair in interphase. However, little is known about the mitotic activities of these enzymes or the exact DNA structures present on UFBs. We focus on the biology of UFBs, with special emphasis on their underlying DNA structure and the decatenation machineries that process UFBs.

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BLM helicase facilitates telomere replication during leading strand synthesis of telomeres

Abstract: BLM helicase facilitates telomere replication by resolving G-quadruplex structures that can form in the G-rich repeats during leading strand synthesis.

Cited by 133 publications

References 60 publications

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

Knotty Problems during Mitosis: Mechanistic Insight into the Processing of Ultrafine DNA Bridges in Anaphase

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