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Examination of Proteins Bound to Nascent DNA in Mammalian Cells Using BrdU-ChIP-Slot-Western Technique
Published on: January 14, 2016
RBM45 competes with HDAC1 for binding to FUS in response to DNA damage
Juanjuan Gong1, Min Huang2, Fengli Wang1
1State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
DNA damage response (DDR) is essential for genome stability and human health. Recently, several RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), have been found unexpectedly to modulate this process. The role of FUS in DDR is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Given that RBM45 is also an ALS-associated RBP, we wondered whether RBM45 plays any function during this process. Here, we report that RBM45 can be recruited to laser microirradiation-induced DNA damage sites in a PAR- and FUS-dependent manner, but in a RNA-independent fashion. Depletion of RBM45 leads to abnormal DDR signaling and decreased efficiency in DNA double-stranded break repair. Interestingly, RBM45 is found to compete with histone deacetylase 1 (HDAC1) for binding to FUS, thereby regulating the recruitment of HDAC1 to DNA damage sites. A common familial ALS-associated FUS mutation (FUS-R521C) is revealed to prefer to cooperate with RBM45 than HDAC1. Our findings suggest that RBM45 is a key regulator in FUS-related DDR signaling whose dysfunction may contribute to the pathogenesis of ALS.
Insights
RNA binding protein RBM45 regulates DNA damage response (DDR) by interacting with FUS, impacting genome stability and amyotrophic lateral sclerosis (ALS) pathogenesis. Its dysfunction may contribute to ALS development.
Area of Science:
- Molecular Biology
- Genetics
- Neuroscience
Background:
- DNA damage response (DDR) is crucial for maintaining genome stability.
- RNA binding proteins (RBPs), including fused-in-sarcoma (FUS), are increasingly recognized for their roles in DDR.
- FUS dysfunction is linked to amyotrophic lateral sclerosis (ALS) pathogenesis.
Purpose of the Study:
- To investigate the role of RBM45, an ALS-associated RBP, in the DNA damage response.
- To elucidate the mechanism by which RBM45 interacts with FUS during DDR.
- To explore the implications of RBM45-FUS interactions in ALS.
Main Methods:
- Laser microirradiation to induce DNA damage.
- Assessment of RBM45 recruitment to DNA damage sites.
- RNA interference (RNAi) to deplete RBM45.
- Analysis of DNA double-strand break repair efficiency.
- Co-immunoprecipitation assays to study protein-protein interactions.
Main Results:
- RBM45 is recruited to DNA damage sites in a FUS-dependent, RNA-independent manner.
- RBM45 depletion impairs DDR signaling and DNA repair.
- RBM45 competes with HDAC1 for FUS binding, modulating HDAC1 recruitment.
- A familial ALS-associated FUS mutation (FUS-R521C) favors RBM45 over HDAC1 interaction.
Conclusions:
- RBM45 is a key regulator of FUS-mediated DNA damage response.
- RBM45's interaction with FUS is critical for genome stability.
- Dysregulation of RBM45 in DDR may contribute to the development of amyotrophic lateral sclerosis.
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