Regulation of replication fork speed: Mechanisms and impact on genomic stability

Merchut-Maya, Joanna Maria; Bártek, Jiří; Maya-Mendoza, Apolinar

doi:10.1016/j.dnarep.2019.102654

Cited by 27 publications

(21 citation statements)

References 89 publications

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“…Furthermore, we show here that the R-loop accumulation after RTEL1 and Poldip3 depletion occurs at genomic common fragile sites, rDNA and telomeres. Our results reveal a new role of RTEL1 (and Poldip3) in protection against genome instability by preventing excessive R-loop accumulation after replication stress, a condition emerging as a hallmark of cancer and implicated in aging (Halazonetis et al 2008;Merchut-Maya et al 2019), thus providing mechanistic insights into the role of RTEL1 in safeguarding proper genome-wide replication and genomic integrity.…”

mentioning

confidence: 86%

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

et al. 2020

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RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome integrity maintenance. Our results from complementary human cell culture models established that RTEL1 and the Polδ subunit Poldip3 form a complex and are/ function mutually dependent in chromatin binding after replication stress. Loss of RTEL1 and Poldip3 leads to marked R-loop accumulation that is confined to sites of active replication, enhances endogenous replication stress, and fuels ensuing genomic instability. The impact of depleting RTEL1 and Poldip3 is epistatic, consistent with our proposed concept of these two proteins operating in a shared pathway involved in DNA replication control under stress conditions. Overall, our data highlight a previously unsuspected role of RTEL1 and Poldip3 in R-loop suppression at genomic regions where transcription and replication intersect, with implications for human diseases including cancer.

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confidence: 86%

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

et al. 2020

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“…DNA replication stress (RS) is caused by extrinsic and intrinsic factors that disrupt replication fork dynamics, and critically, RS is a major driver of cancer genomic instability [ 307 , 308 ]. Notably, FOXM1 was recently reported to induce DNA replication stress in vitro and FOXM1 expression was observed to correlate with expression of RS biomarkers in several cancer types, including HGSC [ 309 ].…”

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

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“…We may be observing over-resection on the lagging strand in FANCD2 -/cells at early times of fork stalling that leads to reversed forks in our studies. PARPi causes fork speed acceleration and enhanced replication fork speed can in itself cause genome instability and may involve unligated Okazaki fragments (Maya-Mendoza et al, 2018;Merchut-Maya et al, 2019). Knockdown of FANCD2 leads to increased fork speed upon prolonged replication stress conditions (Lossaint et al, 2013;Yeo et al, 2014).…”

Section: The Importance Of Regulating Dna2 Nuclease Activitymentioning

confidence: 99%

FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability

Liu

Roubal

Polaczek

et al. 2021

Preprint

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SummaryFANCD2 protein, a key coordinator and effector of the interstrand crosslink repair pathway, is also required to prevent excessive nascent strand degradation at hydroxyurea induced stalled forks. The mechanisms of the fork protection are not well studied. Here, we purified FANCD2 to study how FANCD2 regulates DNA resection at stalled forks. In vitro, we showed that FANCD2 inhibits fork degradation in two ways: 1) it inhibits DNA2 nuclease activity by directly binding to DNA2. 2) independent of dimerization with FANCI, FANCD2 itself stabilizes RAD51 filaments to inhibit various nucleases, including DNA2. More unexpectedly, FANCD2 acts as a RAD51 mediator to stimulate the strand exchange activity of RAD51, and does so by enhancing ssDNA binding of RAD51. Our work biochemically explains mechanisms by which FANCD2 protects stalled forks and further provides a simple molecular explanation for genetic interactions between FANCD2 and the BRCA2 mediator.

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Regulation of replication fork speed: Mechanisms and impact on genomic stability

Cited by 27 publications

References 89 publications

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability

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