Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

Malewicz, Michal; Kadkhodaei, Banafsheh; Kee, Nigel; Volakakis, Nikolaos; Hellman, Ulf; Viktorsson, Kristina; Leung, Chuen Yan; Chen, Benjamin; Lewensohn, Rolf; Gent, Dik C. van; Chen, David J.; Perlmann, Thomas

doi:10.1101/gad.16872411

Cited by 70 publications

(86 citation statements)

References 33 publications

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“…Similarly, the lines between transcription factors and repair factors have become more blurred. Several other transcription factors, including ATF2, FOXO3a, NR4A, and Sp1, are also known to localize to DSBs and directly stimulate DNA repair and/or checkpoint signaling independently of transcription (Bhoumik et al 2005;Tsai et al 2008;Malewicz et al 2011;Beishline et al 2012;Velez-Cruz and Johnson 2012;Malewicz and Perlmann 2014). Like E2F1, these other transcription factors localize to DSBs independently of their DNA-binding domains, but it is unclear whether they recruit histone-modifying or remodeling enzymes to alter chromatin structure at DSBs.…”

Section: S29a/s29amentioning

confidence: 99%

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

et al. 2016

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The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.

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Section: S29a/s29amentioning

confidence: 99%

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

et al. 2016

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“…Interestingly, the DNA repair action of NR4A receptors is not dependent on their transcriptional activity, but rather due to a direct interaction at the DNA repair site, the precise mechanisms of which remain incompletely understood (18). In melanoma, repression of NR4A receptors impairs UV-induced DNA damage repair via the melanocortin-1 receptor (19).…”

Section: Dna Repairmentioning

confidence: 99%

“…A novel function for NR4A receptors in DNA doublestrand break (DSB) repair has recently been identified (18 NR4A receptors translocate to sites of double-strand DNA damage in a mechanism dependent on PARP-1 and are phosphorylated by DNA protein kinases. Interestingly, the DNA repair action of NR4A receptors is not dependent on their transcriptional activity, but rather due to a direct interaction at the DNA repair site, the precise mechanisms of which remain incompletely understood (18).…”

Section: Dna Repairmentioning

confidence: 99%

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Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

153

138

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Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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“…Eluates were analyzed by SDS-PAGE, gels were subjected to silver stain, and bands of interest were excised for mass spectrometry identifi cation. Mass spectrometry protocol was previously described ( 40 ).…”

Section: Immunoprecipitation and Mass Spectrometrymentioning

confidence: 99%

RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

et al. 2014

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Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. SIGNIFICANCE:KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation. Cancer Discov; 4(4); 434-51.

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Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

Cited by 70 publications

References 33 publications

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

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