bims-myxlip 2023-07-09 papers

Issue of 2023–07–09
three papers selected by
Laura Mannarino, Humanitas Research

Res Sq. 2023 May 29. pii: rs.3.rs-2869150. [Epub ahead of print]

FET fusion oncoproteins disrupt physiologic DNA repair networks and induce ATR synthetic lethality in cancer.

Asmin Tulpule, Shruti Menon, Marcus Breese, Yone Lin, Hannah Allegakoen, Shruthi Perati, Ann Heslin, Max Horlbeck, Jonathan Weissman, Alejandro Sweet-Cordero, Trever Bivona.

The genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations). The broader question of whether and how oncogenes create tumor-specific vulnerabilities within DDR networks remains unanswered. Native FET protein family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DSB repair remains poorly defined. Here we focus on Ewing sarcoma (ES), an EWS-FLI1 fusion oncoprotein-driven pediatric bone tumor, as a model for FET rearranged cancers. We discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native EWS function in activating the DNA damage sensor ATM. Using preclinical mechanistic approaches and clinical datasets, we establish functional ATM deficiency as a principal DNA repair defect in ES and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in FET rearranged cancers. Thus, aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt normal DSB repair, revealing a mechanism for how oncogenes can create cancer-specific synthetic lethality within DDR networks.

DOI: https://doi.org/10.21203/rs.3.rs-2869150/v1

Biopolymers. 2023 Jul 03. e23558

Conformational fluctuations and phases in fused in sarcoma (FUS) low-complexity domain.

D Thirumalai, Abhinaw Kumar, Debayan Chakraborty, John E Straub, Mauro L Mugnai.

The well-known phenomenon of phase separation in synthetic polymers and proteins has become a major topic in biophysics because it has been invoked as a mechanism of compartment formation in cells, without the need for membranes. Most of the coacervates (or condensates) are composed of Intrinsically Disordered Proteins (IDPs) or regions that are structureless, often in interaction with RNA and DNA. One of the more intriguing IDPs is the 526-residue RNA-binding protein, Fused in Sarcoma (FUS), whose monomer conformations and condensates exhibit unusual behavior that are sensitive to solution conditions. By focussing principally on the N-terminus low-complexity domain (FUS-LC comprising residues 1-214) and other truncations, we rationalize the findings of solid-state NMR experiments, which show that FUS-LC adopts a non-polymorphic fibril structure (core-1) involving residues 39-95, flanked by fuzzy coats on both the N- and C-terminal ends. An alternate structure (core-2), whose free energy is comparable to core-1, emerges only in the truncated construct (residues 110-214). Both core-1 and core-2 fibrils are stabilized by a Tyrosine ladder as well as hydrophilic interactions. The morphologies (gels, fibrils, and glass-like) adopted by FUS seem to vary greatly, depending on the experimental conditions. The effect of phosphorylation is site-specific. Simulations show that phosphorylation of residues within the fibril has a greater destabilization effect than residues that are outside the fibril region, which accords well with experiments. Many of the peculiarities associated with FUS may also be shared by other IDPs, such as TDP43 and hnRNPA2. We outline a number of problems for which there is no clear molecular explanation.

Keywords: FUS excited states; fibril morphology depends on length; phosphorylation is site-specific

DOI: https://doi.org/10.1002/bip.23558