UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.Control of MRE11 association with chromatin by UBQLN4 during double-strand break repair influences repair pathway choice and can be dysregulated in tumorigenesis.This work was funded through the Dr. M. and S.G. Adelson Medical Research Foundation, The Israel Science Foundation joint ISF-NSFC Research Program and The Israel Cancer Research Fund (to Y.S.), the German-Israeli Foundation for Research and Development (I-65-412.20-2016 to Y.S. and H.C.R.), the Deutsche Forschungsgemeinschaft (KFO-286-RP2 to H.C.R., KFO-286-CP2 to M.P., JA2439/1-1 to R.D.J., DI1731/2-1 to F.D.), the Else Kröner-Fresenius Stiftung (2014-A06 to H.C.R., 2016_Kolleg.19 to R.D.J.), the Deutsche Krebshilfe (1117240 to H.C.R. and the Mildred-Scheel Professorship to M.P.), the German Ministry of Education and Research (BMBF 01GM1211B to D.W., BMBF e:Med 01ZX1303A and 01ZX1406 to M.P., BMBF e:Med 01ZX1303 and 01ZX1307 to M.F.), and R+D+I grants from the Spanish Ministry of Economy and Competitivity (SAF2013-43255-P and SAF2016-74855-P to P.H.). Y.S. is a Research Professor of the Israel Cancer Research Fund

Modular and flexible spectral-element waveformmodelling in two and three dimensions

In this paper, we present a series of mathematical abstractions for seismologically relevant wave equations discretized using finite-element methods, and demonstrate how these abstractions can be implemented efficiently in computer code. Our motivation is to mitigate the combinatorial complexity present when considering geophysical waveform modelling and inversion, where a variety of spatial discretizations, material models, and boundary conditions must be considered simultaneously. We accomplish this goal by first considering three distinct classes of abstract mathematical models: (1) those representing the physics of an underlying wave equation, (2) those describing the discretization of the chosen equation onto a finite-dimensional basis and (3) those describing any spatial transforms. A full representation of the discrete wave equation can then be constructed using a hierarchical nesting of models from each class. Additionally, each class is functionally orthogonal to the others, and with certain restrictions models within one class can be interchanged independently from changes in another. We then show how this recasting of the relevant equations can be implemented concisely in computer software using an abstract object-oriented design, and discuss how recent developments in the numerical and computational sciences can be naturally incorporated. This builds to a set of results where we demonstrate how the developments presented can lead to an implementation capable of multiphysics waveform simulations in completely unstructured domains, on both hypercubical and simplical spectral-element meshes, in both two and three dimensions, while remaining concise, efficient and maintainable.ISSN:0956-540XISSN:1365-246