The splicing-factor related protein SFPQ/PSF interacts with RAD51D and is necessary for homology-directed repair and sister chromatid cohesion

Abstract

DNA double-stranded breaks (DSBs) are among the most severe forms of DNA damage and responsible for chromosomal translocations that may lead to gene fusions. The RAD51 family plays an integral role in preserving genome stability by homology directed repair of DSBs. From a proteomics screen, we recently identified SFPQ/PSF as an interacting partner with the RAD51 paralogs, RAD51D, RAD51C and XRCC2. Initially discovered as a potential RNA splicing factor, SFPQ was later shown to have homologous recombination and non-homologous end joining related activities and also to bind and modulate the function of RAD51. Here, we demonstrate that SFPQ interacts directly with RAD51D and that deficiency of both proteins confers a severe loss of cell viability, indicating a synthetic lethal relationship. Surprisingly, deficiency of SFPQ alone also leads to sister chromatid cohesion defects and chromosome instability. In addition, SFPQ was demonstrated to mediate homology directed DNA repair and DNA damage response resulting from DNA crosslinking agents, alkylating agents and camptothecin. Taken together, these data indicate that SFPQ association with the RAD51 protein complex is essential for homologous recombination repair of DNA damage and maintaining genome integrity.

PARP1-Driven Poly-ADP-Ribosylation Regulates BRCA1 Function in Homologous Recombination–Mediated DNA Repair

“…These proteins can be portrayed as a network of communicating polypeptides, based upon their gene ontology terms and their experimentally deciphered protein interaction properties (14). Among their interacting partners are proteins recently shown to be involved in cellular responses to DSBs, including SFPQ (15), CHD4 (16), and UBR5 (17) (Supplementary Fig. S1c).…”

Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography

“…Knockdown in stably transfected HCT116 cells results in elevated IR-induced chromosomal aberrations and increased sensitivity to killing [767]. PSF is also reported to interact directly with RAD51D in vitro and to play a role in maintaining sister chromatid cohesion [1193]. Additional proteins that interact with RAD51 and its paralogs are being identified [1194].…”

DDX54 regulates transcriptome dynamics during DNA damage response

“…Several recent large-scale proteomic studies have reported that RNA processing and translation factors are post-translationally modified by DDR signaling (Matsuoka et al 2007;Bennetzen et al 2010;Bensimon et al 2010;Beli et al 2012;Jungmichel et al 2013), and many RBPs are essential for the DDR (Paulsen et al 2009;Adamson et al 2012;Boucas et al 2015). Specifically, some RNA processing factors (EWSR1, THRAP3, RBMX, NONO, HRNPC, YBX1, RBM14) can be either recruited to DSBs, relocalized upon DNA damage and/or directly contribute to DNA repair (Paronetto et al 2011;Rajesh et al 2011;Adamson et al 2012;Beli et al 2012;Krietsch et al 2012;Polo et al 2012;Anantha et al 2013;Chang et al 2014;Shkreta and Chabot 2015;Simon et al 2017), whereas others such as SRSF10 impact alternative splicing of transcripts coding for proteins involved in DNA repair, cell cycle control, and apoptosis (Shkreta et al 2016). Notably, somatic mutations very often occur in genes encoding RNA splicing factors, thus leading to widespread misregulated splicing events in many tumor types (Sebestyén et al 2016).…”