The RNA Processing Factor Y14 Participates in DNA Damage Response and Repair

Abstract

SummaryDNA repair deficiency leads to genome instability and hence human disease. Depletion of the RNA processing factor Y14/RBM8A in cultured cells or Rbm8a haplodeficiency in the developing mouse cortex results in the accumulation of DNA damage. Y14 depletion differentially affected the expression of DNA damage response (DDR) factors and induced R-loops, both of which threaten genomic stability. Immunoprecipitation coupled with mass spectrometry revealed DDR factors as potential Y14-interacting partners. Further results confirmed that Y14 interacts with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionated with Ku in chromatin-enriched fractions and further accumulated on chromatin upon DNA damage. Y14 knockdown delayed recruitment of DDR factors to DNA damage sites and formation of γH2AX foci and also led to Ku retention on chromatin. Accordingly, Y14 depletion compromised the efficiency of DNA end joining. Therefore Y14 likely plays a direct role in DNA damage repair via its interaction with DDR factors.

A Day in the Life of the Exon Junction Complex

“…Immediately after their synthesis in the cytoplasm, RBM8A and MAGOH assemble into a heterodimer, which is transported by importin 13 (IPO13) to the nucleus [ 21 , 22 ] ( Figure 1 C). Although the heterodimer likely represents the biologically predominant form, RBM8A has also been described to have EJC-independent functions, for example as a factor involved in DNA damage repair and modulator of processing body formation [ 23 , 24 ]. Still, it remains to be investigated to what extent RBM8A and MAGOH have functions separate from each other or as a heterodimer outside the EJC.…”

The Y14-p53 Regulatory Circuit in Megakaryocyte Differentiation and Thrombocytopenia

“…A high frequency of lymphomas has been observed in Trp53 -null mice (Donehower et al, 1995). Because Y14 is also essential for maintaining genome stability (Chuang et al, 2019), concomitant loss of Rbm8a and p53 may likely increase the incidence of cancer.…”

“…Conditional allele of Rbm8a ( Rbm8a f/f ) was created by insertion of loxP sites flanking its exon 2 and 6 using the CRISPR/Cas9 system (Chuang et al, 2019). Rbm8a f/f mice were then crossed with Pf4-Cre +/- mice (Tiedt et al, 2007).…”

“…Depletion of Y14, however, alters mRNA splicing patterns, indicating that Y14 also modulates alternative splicing (Fukumura et al, 2016; Michelle et al, 2012). Moreover, Y14 is involved in DNA damage repair through its direct interaction with the non-homologous end joining machinery (Chuang et al, 2019). Y14 deficiency leads to accumulation of DNA damage and cell-cycle arrest at G2/M phase (Lu et al, 2017).…”

FUS-dependent liquid-liquid phase separation is an early event in double-strand break repair

“…RBPs have been shown to contribute both directly and indirectly to genome stability. For example, the loss of pre-mRNA splicing or mRNA export factors can favour the accumulation of RNA:DNA hybrids (R-loops) that can be processed to DSBs (Chuang et al, 2019;Li and Manley, 2005). In addition, an increasing number of studies have shown that several RBPs are recruited to sites of DNA damage and participate in DSB repair (Mikolaskova et al, 2018).…”