All gaugings and stable de Sitter in D=7 half-maximal supergravity

We study the general formulation of gauged supergravity in seven dimensions with sixteen supercharges keeping duality covariance by means of the embedding tensor formalism. We first classify all inequivalent duality orbits of consistent deformations. Secondly, we analyse the complete set of critical points in a systematic way. Interestingly, we find the first examples of stable de Sitter solutions within a theory with such a large amount of supersymmetry.Comment: 25 pages, 1 figure, 7 table

On Type IIB moduli stabilization and N = 4, 8 supergravities

We analyze D = 4 compactifications of Type IIB theory with generic, geometric and non-geometric, dual fluxes turned on. In particular, we study N = 1 toroidal orbifold compactifications that admit an embedding of the untwisted sector into gauged N = 4, 8 supergravities. Truncations, spontaneous breaking of supersymmetry and the inclusion of sources are discussed. The algebraic identities satisfied by the supergravity gaugings are used to implement the full set of consistency constraints on the background fluxes. This allows to perform a generic study of N = 1 vacua and identify large regions of the parameter space that do not admit complete moduli stabilization. Illustrative examples of AdS and Minkowski vacua are presented.Comment: 48 pages, 1 figure. References added. Published in NP B 849 (2011) pp. 80-11

Gauged Double Field Theory

We find necessary and sufficient conditions for gauge invariance of the action of Double Field Theory (DFT) as well as closure of the algebra of gauge symmetries. The so-called weak and strong constraints are sufficient to satisfy them, but not necessary. We then analyze compactifications of DFT on twisted double tori satisfying the consistency conditions. The effective theory is a Gauged DFT where the gaugings come from the duality twists. The action, bracket, global symmetries, gauge symmetries and their closure are computed by twisting their analogs in the higher dimensional DFT. The non-Abelian heterotic string and lower dimensional gauged supergravities are particular examples of Gauged DFT.Comment: Minor changes, references adde

PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest for targeting BRCA2;p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) through loss of PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, we identify various genes involved in DNA repair to be essential for the survival of PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors of PARG loss. We provide evidence for compromised replication fork progression, DNA single-strand break repair, and Okazaki fragment processing in PARG;BRCA2;p53-deficient cells, alterations that exacerbate the effects of EXO1/FEN1 inhibition and become lethal in this context. Since this sensitivity is dependent on BRCA2 defects, we propose to target EXO1/FEN1 in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy for enhancing the effect of PARG inhibitors in homologous recombination-deficient tumors.</p

DNA-PKcs promotes fork reversal and chemoresistance.

The DNA-PKcs kinase mediates the repair of DNA double-strand breaks via classical non-homologous end joining (NHEJ). DNA-PKcs is also recruited to active replication forks, although a role for DNA-PKcs in the control of fork dynamics is unclear. Here, we identify a crucial role for DNA-PKcs in promoting fork reversal, a process that stabilizes stressed replication forks and protects genome integrity. DNA-PKcs promotes fork reversal and slowing in response to several replication stress-inducing agents in a manner independent of its role in NHEJ. Cells lacking DNA-PKcs activity show increased DNA damage during S-phase and cellular sensitivity to replication stress. Notably, prevention of fork slowing and reversal via DNA-PKcs inhibition efficiently restores chemotherapy sensitivity in BRCA2-deficient mammary tumors with acquired PARPi resistance. Together, our data uncover a new key regulator of fork reversal and show how DNA-PKcs signaling can be manipulated to alter fork dynamics and drug resistance in cancer

Functional Interplay between the 53BP1-Ortholog Rad9 and the Mre11 Complex Regulates Resection, End-Tethering and Repair of a Double-Strand Break

<div><p>The Mre11-Rad50-Xrs2 nuclease complex, together with Sae2, initiates the 5′-to-3′ resection of Double-Strand DNA Breaks (DSBs). Extended 3′ single stranded DNA filaments can be exposed from a DSB through the redundant activities of the Exo1 nuclease and the Dna2 nuclease with the Sgs1 helicase. In the absence of Sae2, Mre11 binding to a DSB is prolonged, the two DNA ends cannot be kept tethered, and the DSB is not efficiently repaired. Here we show that deletion of the yeast 53BP1-ortholog <i>RAD9</i> reduces Mre11 binding to a DSB, leading to Rad52 recruitment and efficient DSB end-tethering, through an Sgs1-dependent mechanism. As a consequence, deletion of <i>RAD9</i> restores DSB repair either in absence of Sae2 or in presence of a nuclease defective MRX complex. We propose that, in cells lacking Sae2, Rad9/53BP1 contributes to keep Mre11 bound to a persistent DSB, protecting it from extensive DNA end resection, which may lead to potentially deleterious DNA deletions and genome rearrangements.</p></div