RBM45 competes with HDAC1 for binding to FUS in response to DNA damage

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.

RNA Binding Motif Protein RBM45 Regulates Expression of the 11-Kilodalton Protein of Parvovirus B19 through Binding to Novel Intron Splicing Enhancers

“…In normal cells, RBM45 is localized predominately in the nucleus (43) and plays a role in double-strand break (DSB) repair (44). Cytoplasm-localized RBM45 has been sug- gested to contribute to neurodegeneration in ALS (45).…”

“…It is localized within the TDP43-positive cytoplasmic inclusions. This evidence suggests that the aggregationinduced loss of normal RBM45 function might also play an important role in ALS pathogenesis (44). The RNA binding sequence of RBM45 has not been defined.…”

“…RBM45, also named drb1, was recently found to be a FUS (fused-in-sarcoma) protein-interacting RNA-binding protein (42). It is localized predominately in the nucleus (43), where it plays an important role in the DNA damage response (DDR) (44). It is recruited to the DNA damage sites in a poly(ADP-ribose) (PAR)-dependent and FUS-dependent manner and promotes dsDNA break repair by preventing histone deacetylase 1 from excessive recruitment.…”

The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

“…Whilst these two mechanisms are often highlighted as being central to ALS, this rather simplistic division does not fully capture the complexity of the range of functions performed by the proteins associated with ALS, nor the cellular signalling pathways that are known to be dysfunctional in this disorder. Recently, DNA damage has been linked to ALS [ 40 , 43 , 44 , 45 , 46 , 47 ]. Interestingly, many of the signalling pathways associated with DNA damage are also implicated in ALS, including oxidative stress, mitochondrial function, RNA metabolism, autophagy, and proteosomal function [ 48 , 49 , 50 , 51 , 52 ].…”

“…DNA repair activity detected by 8-hydroxy-2-deoxyguanosine (OHdG) immunoreactivity is also increased in the motor cortex of sALS patients [ 66 ], and elevated levels of 8-OHdG were also identified in familial ALS spinal cords bearing SOD1 mutations [ 66 ]. Apurinic/apyrimidinic endonuclease 1 (APE1) is elevated in the brain and spinal cord of sporadic ALS patients [ 45 ]. Activation of cellular DNA repair processes has been previously implicated in motor neuron degeneration [ 61 , 67 ], and mice lacking the gene encoding ERCC1, which is essential for SSB nucleotide excision repair and repair of DSBs, show age-related motor dysfunction [ 68 ].…”