Proteomic identification of PSF and p54(nrb) as topBP1‐interacting proteins

Kuhnert, Anja; Schmidt, Frank; Monajembashi, Shamci; Franke, Claudia; Schlott, Bernhard; Grosse, Frank; Greulich, Karl Otto; Saluz, Hans‐Peter; Hänel, F.

doi:10.1002/jcb.24045

Cited by 19 publications

(17 citation statements)

References 40 publications

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“…Within this small region of p54 nrb , the residue of tyrosine-267 (Y267) is conserved among all species (Figure 3a), and has been proposed to play a role in the interaction with PSPC1. 33 To determine whether Y267 is important for p54 nrb binding to nSREBP-1a, we mutated this residue to alanine (Y267A) and performed GST pulldown assays. As shown in Figure 3d, while the wild-type (WT) p54 nrb could bind to nSREBP-1a, the Y267A mutant p54 nrb could not, suggesting that the Y267 residue is essential for p54 nrb binding to nSREBP-1a in vitro.…”

Section: Resultsmentioning

confidence: 99%

p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A

Zhu

Zhao

et al. 2015

Oncogene

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Dysregulation of lipid metabolism is common in breast cancer. However, the underlying mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of breast cancer is poorly understood. Here, we show that the nuclear protein p54(nrb)/Nono is highly expressed in breast cancer tissues as compared with the adjacent normal tissues in human patients. To determine the functions of p54(nrb) in breast cancer, we performed a biochemical screen and identified SREBP-1a, a master activator for genes involved in lipid biosynthesis, as a novel interacting protein of p54(nrb). In human breast cancer tissues, the levels of p54(nrb) and SREBP-1a proteins were positively correlated with each other. Our biochemical analyses showed that the conserved Y267 residue of p54(nrb) was required for its binding to the nuclear form of SREBP-1a. Interestingly, p54(nrb) binding to nuclear SREBP-1a caused an increase of nuclear SREBP-1a protein stability. As a result, p54(nrb) stimulates SREBP-1-meidated transcription of lipogenic genes and lipid production in breast cancer cells. Moreover, both p54(nrb) and SREBP-1a were required for breast cancer cell growth in vitro, and p54(nrb) binding to nuclear SREBP-1a was also critical for breast tumor development in vivo. Together, we conclude that p54(nrb) is a novel regulator of SREBP-1a in the nucleus, and our data suggest that p54(nrb) regulation of SREBP-1a supports the increased cellular demand of lipids for breast cancer growth. Thus, the SREBP pathway may represent a novel target for treating breast cancer.

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Section: Resultsmentioning

confidence: 99%

p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A

Zhu

Zhao

et al. 2015

Oncogene

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“…SFPQ promotes homologous DNA-pairing, strand invasion, D-loop formation and topoisomerase activity in a variety of cell types ( 116 – 119 ). SFPQ/NONO is found within the DSB preligation complex with the Ku protein and substrate DNA ( 120 ) and directly interacts with RAD51 ( 50 , 121 ), TopBP1 ( 122 ) and Matrin3 ( 123 ), recruiting proteins to sites of DNA damage ( 114 ) and stimulating both homologous and nonhomologous repair ( 41 , 50 , 121 , 123 , 124 ). Collectively, the DBHS proteins promote end joining of homologous DNA by direct interaction with DNA ends and recruitment/stabilization of a preligation complex ( 125 ).…”

Section: Subnuclear Structures and Complexesmentioning

confidence: 99%

The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold

2016

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Nuclear proteins are often given a concise title that captures their function, such as ‘transcription factor,’ ‘polymerase’ or ‘nuclear-receptor.’ However, for members of the Drosophila behavior/human splicing (DBHS) protein family, no such clean-cut title exists. DBHS proteins are frequently identified engaging in almost every step of gene regulation, including but not limited to, transcriptional regulation, RNA processing and transport, and DNA repair. Herein, we present a coherent picture of DBHS proteins, integrating recent structural insights on dimerization, nucleic acid binding modalities and oligomerization propensity with biological function. The emerging paradigm describes a family of dynamic proteins mediating a wide range of protein–protein and protein–nucleic acid interactions, on the whole acting as a multipurpose molecular scaffold. Overall, significant steps toward appreciating the role of DBHS proteins have been made, but we are only beginning to understand the complexity and broader importance of this family in cellular biology.

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“…The pleiotropic PSF protein is mobilized to lesions after laser-induced DNA damage [ 140 ] ( Figure 5 ). PSF displays in vitro DSB end-rejoining activity [ 141 ], and is implicated in NHEJ and HR repair pathways [ 140 , 142 , 143 ]. PSF forms a complex with NONO, a protein that binds to PAR and is implicated in NHEJ and HR [ 43 , 144 ].…”

Section: Exclusion and Recruitment Of Splicing Factors At Sites Ofmentioning

confidence: 99%

The RNA Splicing Response to DNA Damage

2015

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The number of factors known to participate in the DNA damage response (DDR) has expanded considerably in recent years to include splicing and alternative splicing factors. While the binding of splicing proteins and ribonucleoprotein complexes to nascent transcripts prevents genomic instability by deterring the formation of RNA/DNA duplexes, splicing factors are also recruited to, or removed from, sites of DNA damage. The first steps of the DDR promote the post-translational modification of splicing factors to affect their localization and activity, while more downstream DDR events alter their expression. Although descriptions of molecular mechanisms remain limited, an emerging trend is that DNA damage disrupts the coupling of constitutive and alternative splicing with the transcription of genes involved in DNA repair, cell-cycle control and apoptosis. A better understanding of how changes in splice site selection are integrated into the DDR may provide new avenues to combat cancer and delay aging.

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Proteomic identification of PSF and p54(nrb) as topBP1‐interacting proteins

Cited by 19 publications

References 40 publications

p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A

p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A

The DBHS proteins SFPQ, NONO and PSPC1: a multipurpose molecular scaffold

The RNA Splicing Response to DNA Damage

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