Publications by authors named "Andrés Herrero-Ruiz"

4 Publications

  • Page 1 of 1

Topoisomerase IIα represses transcription by enforcing promoter-proximal pausing.

Cell Rep 2021 Apr;35(2):108977

Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla 41092, Spain; Topology and DNA Breaks Group, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain. Electronic address:

Accumulation of topological stress in the form of DNA supercoiling is inherent to the advance of RNA polymerase II (Pol II) and needs to be resolved by DNA topoisomerases to sustain productive transcriptional elongation. Topoisomerases are therefore considered positive facilitators of transcription. Here, we show that, in contrast to this general assumption, human topoisomerase IIα (TOP2A) activity at promoters represses transcription of immediate early genes such as c-FOS, maintaining them under basal repressed conditions. Thus, TOP2A inhibition creates a particular topological context that results in rapid release from promoter-proximal pausing and transcriptional upregulation, which mimics the typical bursting behavior of these genes in response to physiological stimulus. We therefore describe the control of promoter-proximal pausing by TOP2A as a layer for the regulation of gene expression, which can act as a molecular switch to rapidly activate transcription, possibly by regulating the accumulation of DNA supercoiling at promoter regions.
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http://dx.doi.org/10.1016/j.celrep.2021.108977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052185PMC
April 2021

ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links.

Science 2017 09 14;357(6358):1412-1416. Epub 2017 Sep 14.

Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA.

Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
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http://dx.doi.org/10.1126/science.aam6468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623066PMC
September 2017

TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.

Nat Commun 2017 08 10;8(1):233. Epub 2017 Aug 10.

Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9RQ, UK.

DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.
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http://dx.doi.org/10.1038/s41467-017-00307-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550487PMC
August 2017

Regulation of human polλ by ATM-mediated phosphorylation during non-homologous end joining.

DNA Repair (Amst) 2017 03 17;51:31-45. Epub 2017 Jan 17.

Departamento Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Sevilla 41092, Spain; Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla/CSIC, Sevilla 41092, Spain. Electronic address:

DNA double strand breaks (DSBs) trigger a variety of cellular signaling processes, collectively termed the DNA-damage response (DDR), that are primarily regulated by protein kinase ataxia-telangiectasia mutated (ATM). Among DDR activated processes, the repair of DSBs by non-homologous end joining (NHEJ) is essential. The proper coordination of NHEJ factors is mainly achieved through phosphorylation by an ATM-related kinase, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the molecular basis for this regulation has yet to be fully elucidated. In this study we identify the major NHEJ DNA polymerase, DNA polymerase lambda (Polλ), as a target for both ATM and DNA-PKcs in human cells. We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. Molecular evidence suggests that Polλ phosphorylation might favor Polλ interaction with the DNA-PK complex at DSBs. Altogether, our work provides the first demonstration of how Polλ is regulated by phosphorylation to connect with the NHEJ core machinery during DSB repair in human cells.
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http://dx.doi.org/10.1016/j.dnarep.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444907PMC
March 2017