CUT Domain Proteins in DNA Repair and Cancer

Ramdzan, Zubaidah M.; Vickridge, Elise; Faraco, Camila Cristina Fraga; Nepveu, Alain

doi:10.3390/cancers13122953

Cited by 15 publications

(11 citation statements)

References 103 publications

(212 reference statements)

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“…As an upstream component of the Ras-MAPK pathway, the EGFR ligand EREG is a particularly interesting candidate for further studies of the mechanisms of NS-CM. The observed increase in CUX2 expression may also be related to Ras-MAPK hyperactivation, as CUT domain proteins have been shown to accelerate DNA repair and prevent senescence in cells with elevated reactive oxygen species (ROS) levels because of increased Ras signaling ( Ramdzan et al., 2014 , 2021 ). We also found high multinucleation in NS-CM LV cardiomyocytes, which was recapitulated in PTPN11 N308S/+ iPSC-CMs.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

et al. 2022

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Summary Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

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Section: Discussionmentioning

confidence: 99%

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

et al. 2022

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“…On the other hand, several BER enzymes including Pol β, APE1 and FEN1 were found to be overexpressed in multiple cancers ( 16–24 ). Likewise, aberrant or increased expression of the BER accessory factors CUX1, CUX2 and SATB1 were reported in multiple tumours and cancer cell lines (reviewed in ( 25 )). Notably, knockdown of these BER accessory factors was shown to be synthetic lethal in cell lines that exhibit high levels of reactive oxygen species ( 26–30 ).…”

Section: Introductionmentioning

confidence: 97%

The DNA repair function of BCL11A suppresses senescence and promotes continued proliferation of triple-negative breast cancer cells

et al. 2022

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We identified the BCL11A protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro, DNA repair assays demonstrate that both BCL11A and a small recombinant BCL11A160–520 protein that is devoid of DNA binding and transcription regulatory domains can stimulate the enzymatic activities of two base excision repair enzymes: NTHL1 and DNA Pol β. Increased DNA repair efficiency, in particular of the base excision repair pathway, is essential for many cancer cells to proliferate in the presence of elevated reactive oxygen species (ROS) produced by cancer-associated metabolic changes. BCL11A is highly expressed in triple-negative breast cancers (TNBC) where its knockdown was reported to reduce clonogenicity and cause tumour regression. We show that BCL11A knockdown in TNBC cells delays repair of oxidative DNA damage, increases the number of oxidized bases and abasic sites in genomic DNA, slows down proliferation and induces cellular senescence. These phenotypes are rescued by ectopic expression of the short BCL11A160–520 protein. We further show that the BCL11A160–520 protein accelerates the repair of oxidative DNA damage and cooperates with RAS in cell transformation assays, thereby enabling cells to avoid senescence and continue to proliferate in the presence of high ROS levels.

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“…The antimalaria mechanism of ART, which includes iron accumulation and ROS production, has led researchers to wonder whether this approach applies to antitumor therapy [ 71 , 73 , 74 ]. Many studies have demonstrated that tumor tissues exhibit increased levels of ROS than normal tissues [ 109 – 111 ]. However, under sustained oxidative stress, tumor cells become well-adapted to such stress through a set of mechanisms, and they often have defects in cell death executioner mechanisms, which is one of the main causes of therapy resistance.…”

Section: Discussionmentioning

confidence: 99%

The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer

Guo

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice.

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CUT Domain Proteins in DNA Repair and Cancer

Cited by 15 publications

References 103 publications

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome

The DNA repair function of BCL11A suppresses senescence and promotes continued proliferation of triple-negative breast cancer cells

The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer

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