Scorpins in the DNA Damage Response

Abstract

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells. However, the identification of molecular determinants directing cancer cells toward recovery or death upon DNA damage is still far from complete, and it is object of intense investigation. SPRY-containing RAN binding Proteins (Scorpins) RANBP9 and RANBP10 are evolutionarily conserved and ubiquitously expressed proteins whose biological functions are still debated. RANBP9 has been previously implicated in cell proliferation, survival, apoptosis and migration. Recent studies also showed that RANBP9 is involved in the Ataxia Telangiectasia Mutated (ATM) signaling upon DNA damage. Accordingly, cells lacking RANBP9 show increased sensitivity to genotoxic treatment. Although there is no published evidence, extensive protein similarities suggest that RANBP10 might have partially overlapping functions with RANBP9. Like RANBP9, RANBP10 bears sites putative target of PIK-kinases and high throughput studies found RANBP10 to be phosphorylated following genotoxic stress. Therefore, this second Scorpin might be another overlooked player of the DDR alone or in combination with RANBP9. This review focuses on the relatively unknown role played by RANBP9 and RANBP10 in responding to genotoxic stress.

Keywords: CTLH complex; DDR; GID complex; RANBP10; RANBP9; RANBPM; Scorpins.

Figure 1

Schematic representation of RANBP9 and RANBP10 proteins. RANBP10 shares high amino acid conservation with RANBP9 in the PRY (94%), SPRY (97%), LisH (82%), CTLH (90%), and CRA (89%) domains. The two proteins differ the most at the N-terminus and in the post-CTLH region, which contains several putative PIK-kinase phosphorylation sites (see Table 1). PRD (red)= Proline-Rich Domain; PRY/SPRY (light blue) = Spore lysis A and Ryanodine receptor Domain; LisH (green) = Lissencephaly type-I-like homology motif; CTLH (yellow) = Carboxy-terminal to LisH motif domain; CRA (orange) = CT11-RanBP9 domain; dark blue = putative Nuclear Localization Signal; Tub (purple) = tubulin-binding domain.

Figure 2

Schematic representation of the S. cerevisiae Glucose-Induced degradation Deficient (GID)- and correspondent mammalian CTLH-macromolecular complexes. (A) The topology of the GID complex in yeast is well established [31]; (B) Predicted composition of the mammalian CTLH complex based on the GID mammalian homologs. The name of the complex comes from the CTLH domain that most of the members have; (C) CTLH or Nuclear Receptor coregulator-complex pulled down from mammalian cells including RANBP9 and RANBP10 (adapted from [29]). In the depicted complex, GID8 is named C20orf11 and indicated as C20. The experiment showed as part of the complex also YPEL5 (Yippee Like 5) indicated as Y5 in the cartoon, which has no known equivalent in the S. cerevisiae GID complex.

Figure 3

Potential action mechanism of RANBP9 in ATM-dependent DDR. In RANBP9 (red) expressing cells and in the absence of DNA damage (left panel, top), RANBP9 protein shuttles between the nucleus and the cytoplasm. Upon DNA damage such as IR and DNA-damaging drugs (left panel, bottom), ATM is activated and enhances RANBP9 nuclear accumulation through its phosphorylation, potentially with other cytoplasmic partners (purple). This event potentially leads to enhanced KAT5-dependent ATM acetylation, a marker of its full activation. For this reason, RANBP9-expressing cells activate an efficient ATM signaling pathway, resulting in efficient DNA repair and survival to genotoxic stress. Conversely, when RANBP9 expression is reduced, the full activation of ATM is impaired, leading to inefficient DNA repair and sensitivity to DNA damaging agents.