Steger M.,University of Zurich |
Murina O.,University of Zurich |
Huhn D.,University of Zurich |
Ferretti L.P.,University of Zurich |
And 11 more authors.
Molecular Cell | Year: 2013
The regulation of DNA double-strand break (DSB) repair by phosphorylation-dependent signaling pathways is crucial for the maintenance of genome stability; however, remarkably little is known about the molecular mechanisms by which phosphorylation controls DSB repair. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, interacts with key DSB repair factors and affects the relative contributions of homologous recombination (HR) and nonhomologous end-joining (NHEJ) to DSB repair. We find that PIN1-deficient cells display reduced NHEJ due to increased DNA end resection, whereas resection and HR are compromised in PIN1-overexpressing cells. Moreover, we identify CtIP as a substrate of PIN1 and show that DSBs become hyperresected in cells expressing a CtIP mutant refractory to PIN1 recognition. Mechanistically, we provide evidence that PIN1 impinges on CtIP stability by promoting its ubiquitylation and subsequent proteasomal degradation. Collectively, these data uncover PIN1-mediated isomerization as a regulatory mechanism coordinating DSB repair. © 2013 Elsevier Inc.
Kowalczyk M.S.,Weatherall Institute of Molecular Medicine |
Hughes J.R.,Weatherall Institute of Molecular Medicine |
Garrick D.,Weatherall Institute of Molecular Medicine |
Lynch M.D.,Weatherall Institute of Molecular Medicine |
And 17 more authors.
Molecular Cell | Year: 2012
A substantial amount of organismal complexity is thought to be encoded by enhancers which specify the location, timing, and levels of gene expression. In mammals there are more enhancers than promoters which are distributed both between and within genes. Here we show that activated, intragenic enhancers frequently act as alternative tissue-specific promoters producing a class of abundant, spliced, multiexonic poly(A) + RNAs (meRNAs) which reflect the host gene's structure. meRNAs make a substantial and unanticipated contribution to the complexity of the transcriptome, appearing as alternative isoforms of the host gene. The low protein-coding potential of meRNAs suggests that many meRNAs may be byproducts of enhancer activation or underlie as-yet-unidentified RNA-encoded functions. Distinguishing between meRNAs and mRNAs will transform our interpretation of dynamic changes in transcription both at the level of individual genes and of the genome as a whole. © 2012 Elsevier Inc..
Clocchiatti A.,University of Udine |
Di Giorgio E.,University of Udine |
Demarchi F.,Laboratorio Nazionale CIB |
Brancolini C.,University of Udine
Cellular Signalling | Year: 2013
The class IIa deacetylase HDAC4 is unequivocally known as a negative regulator of MEF2-dependent transcription. In the past years several works have allowed us to understand how different signals, mirroring specific environmental circumstances keep in check the repressive action of HDAC4 against MEF2s. At the same time, pieces of evidence have gradually accumulated about HDAC4 activities emancipated from MEF2s. The aim of this review is to discuss about these "unconventional functions" of HDAC4. © 2012 Elsevier Inc.
Bisso A.,Laboratorio Nazionale CIB |
Bisso A.,University of Trieste |
Bisso A.,Italian Institute of Technology |
Faleschini M.,Laboratorio Nazionale CIB |
And 10 more authors.
Cell Cycle | Year: 2013
Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types. © 2013 Landes Bioscience.
Mantovani F.,Laboratorio Nazionale CIB |
Mantovani F.,University of Trieste |
Drost J.,Netherlands Cancer Institute |
Voorhoeve P.M.,National University of Singapore |
And 4 more authors.
Cell Cycle | Year: 2010
Oncogene-induced senescence (OIS) is a cellular defense mechanism against excessive mitogenic signaling and tumorigenesis. One of the major pathways required for OIS is the p53 tumor suppressor pathway. Consequently, many human tumors harbor p53 mutations while others show a dysfunctional p53 pathway, frequently by unknown mechanisms. We recently identified BRD7 as a potential tumor suppressor gene acting as a transcriptional cofactor for p53, affecting histone acetylation, p53 acetylation, and promoter activity on a subset of p53 target genes. We further found low BRD7 expression specifically in a subgroup of human breast tumors harboring wild-type, but not mutant, p53 and showed that one of the responsible mechanisms is deletion of the BRD7 gene locus. Here we further discuss the role of BRD7 as a cofactor in transcriptional regulation and highlight its role as a tumor suppressor via association with p53 and other tumor suppressor proteins. © 2010 Landes Bioscience.