RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability

Chen, Edwin; Ahn, Jong Sook; Sykes, David B.; Breyfogle, Lawrence J.; Godfrey, Anna L.; Nangalia, Jyoti; Ko, Amy; DeAngelo, Daniel J.; Green, Anthony; Mullally, Ann

doi:10.1016/j.celrep.2015.11.037

Cited by 29 publications

(31 citation statements)

References 26 publications

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“…Consistent with the sensitivity to CPT caused by the loss of RECQL5, it has been proposed that RECQL5 helps replication fork reversal, probably through promoting the formation of double helix between two newly synthesized strands at a stalled replication fork. 16,19,21,22 Here, we report that RECQL5 is required for the maintenance of genome stability of TNBC cells. Compromising its function in TNBC cells results in persistence of DNA damage, G2 arrest, and ultimately, cessation of proliferation.…”

Section: Introductionmentioning

confidence: 82%

“…Loss of RECQL5 also results in hypersensitivity to camptothecin (CPT), an inhibitor of topoisomerase I (Top I), but not to other DSB‐causing agents, in mouse cells and human cancer cells, suggesting that RECQL5 plays an important role in dealing with replication stress. Consistent with the sensitivity to CPT caused by the loss of RECQL5, it has been proposed that RECQL5 helps replication fork reversal, probably through promoting the formation of double helix between two newly synthesized strands at a stalled replication fork …”

Section: Introductionmentioning

confidence: 85%

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RECQL5 plays an essential role in maintaining genome stability and viability of triple‐negative breast cancer cells

et al. 2019

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Triple‐negative breast cancer (TNBC) is a malignancy that currently lacks targeted therapies. The majority of TNBCs can be characterized as basal‐like and has an expression profile enriched with genes involved in DNA damage repair and checkpoint response. Here, we report that TNBC cells are under replication stress and are constantly generating DNA double‐strand breaks, which is not seen in non‐TNBC cells. Consequently, we found that RECQL5 , which encodes a RecQ family DNA helicase involved in many aspects of DNA metabolism including replication and repair, was essential for TNBC cells to survive and proliferate in vitro and in vivo. Compromising RECQL5 function in TNBC cells results in persistence of DNA damage, G2 arrest, and ultimately, cessation of proliferation. Our results suggest RECQL5 may be a potential therapeutic target for TNBC.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 85%

RECQL5 plays an essential role in maintaining genome stability and viability of triple‐negative breast cancer cells

et al. 2019

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“…RECQL5 is overexpressed in these cells and appears to contribute to maintaining their genomic stability with depletion of RECQL5 leading to increased replication stress, double strand breaks, replication fork collapse and sensitization to hydroxyurea (24) which is commonly used to treat MPN. Thus, there exists the potential to develop compounds targeting RECQL5A to treat patients with MPN.…”

Section: Introductionmentioning

confidence: 99%

Insights into the RecQ helicase mechanism revealed by the structure of the helicase domain of human RECQL5

et al. 2017

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RecQ helicases are important maintainers of genome integrity with distinct roles in almost every cellular process requiring access to DNA. RECQL5 is one of five human RecQ proteins and is particularly versatile in this regard, forming protein complexes with a diverse set of cellular partners in order to coordinate its helicase activity to various processes including replication, recombination and DNA repair. In this study, we have determined crystal structures of the core helicase domain of RECQL5 both with and without the nucleotide ADP in two distinctly different (‘Open’ and ‘Closed’) conformations. Small angle X-ray scattering studies show that the ‘Open’ form of the protein predominates in solution and we discuss implications of this with regards to the RECQL5 mechanism and conformational changes. We have measured the ATPase, helicase and DNA binding properties of various RECQL5 constructs and variants and discuss the role of these regions and residues in the various RECQL5 activities. Finally, we have performed a systematic comparison of the RECQL5 structures with other RecQ family structures and based on these comparisons we have constructed a model for the mechano-chemical cycle of the common catalytic core of these helicases.

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“…According to a recent study, the factor that maintains fork stability of JAK2 V617F-expressing cells in the proliferative phase of MPN is a DNA helicase RECQL5 [92]. Increased RECQL5 expression protected JAK2 V617F-positive erythroblasts from DSB formation and cell death through increased single-stranded annealing-mediated DNA repair, thus contributing to genomic stability.…”

Section: Role Of Ddr In Polycythemia Veramentioning

confidence: 99%

“…Increased RECQL5 expression protected JAK2 V617F-positive erythroblasts from DSB formation and cell death through increased single-stranded annealing-mediated DNA repair, thus contributing to genomic stability. RECQL5 was shown to be a transcriptional target of JAK2 V617F/STAT5, and its knockdown sensitized JAK2 V617F-expressing cells to hydroxyurea [92].…”

Section: Role Of Ddr In Polycythemia Veramentioning

confidence: 99%

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

Stetka

Gurský

Velasquez

et al. 2020

Cancers

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Inflammatory and oncogenic signaling, both known to challenge genome stability, are key drivers of BCR-ABL-positive chronic myeloid leukemia (CML) and JAK2 V617F-positive chronic myeloproliferative neoplasms (MPNs). Despite similarities in chronic inflammation and oncogene signaling, major differences in disease course exist. Although BCR-ABL has robust transformation potential, JAK2 V617F-positive polycythemia vera (PV) is characterized by a long and stable latent phase. These differences reflect increased genomic instability of BCR-ABL-positive CML, compared to genome-stable PV with rare cytogenetic abnormalities. Recent studies have implicated BCR-ABL in the development of a "mutator" phenotype fueled by high oxidative damage, deficiencies of DNA repair, and defective ATR-Chk1-dependent genome surveillance, providing a fertile ground for variants compromising the ATM-Chk2-p53 axis protecting chronic phase CML from blast crisis. Conversely, PV cells possess multiple JAK2 V617F-dependent protective mechanisms, which ameliorate replication stress, inflammation-mediated oxidative stress and stress-activated protein kinase signaling, all through up-regulation of RECQL5 helicase, reactive oxygen species buffering system, and DUSP1 actions. These attenuators of genome instability then protect myeloproliferative progenitors from DNA damage and create a barrier preventing cellular stress-associated myelofibrosis. Therefore, a better understanding of BCR-ABL and JAK2 V617F roles in the DNA damage response and disease pathophysiology can help to identify potential dependencies exploitable for therapeutic interventions.CML is characterized by an indolent, chronic phase (CP) preceding an acute transformation to BC. Failure of DNA damage repair and loss or malfunction of DDR components accompanied by accumulation of DNA damage and genomic instability has been considered in CML evolution [38,39]. It was proposed that BCR-ABL-expressing cells feature reduced activation of the ATR-Chk1-mediated DDR signaling, with ensuing accumulation of substantial genomic instability due to replication stress and oxidative damage. Mechanistically, such disruption of ATR-dependent signaling was attributed to nuclear import of BCR-ABL after DNA damage and its binding to ATR [40]. However, contrasting data were also reported, showing that BCR-ABL does activate ATR-Chk1 signaling, reflecting responsiveness of BCR-ABL-positive myeloid cells to DNA damage following genotoxic treatment [41]. Some studies also addressed functionality of the ATM-Chk2 signaling axis in CML. Thus, c-Abl is a nuclear tyrosine kinase activated by DNA damage in an ATM-dependent manner [42,43]. Even though the BCR-ABL is predominantly localized to the cytoplasm [44], the aforementioned ability of BCR-ABL translocation to the nucleus after DNA damage led to a proposal that BCR-ABL and c-Abl share multiple protein interactions including that with ATM [40]. As a consequence, ATM-mediated activatory phosphorylation of Chk2 was detected in BCR-ABL-expressing cellular models and...

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RECQL5 Suppresses Oncogenic JAK2-Induced Replication Stress and Genomic Instability

Cited by 29 publications

References 26 publications

RECQL5 plays an essential role in maintaining genome stability and viability of triple‐negative breast cancer cells

RECQL5 plays an essential role in maintaining genome stability and viability of triple‐negative breast cancer cells

Insights into the RecQ helicase mechanism revealed by the structure of the helicase domain of human RECQL5

Role of DNA Damage Response in Suppressing Malignant Progression of Chronic Myeloid Leukemia and Polycythemia Vera: Impact of Different Oncogenes

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