@misc{10481/69143,
year = {2021},
month = {2},
url = {http://hdl.handle.net/10481/69143},
abstract = {Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/
activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic
to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their
use could be expanded.
Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient
samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes.
Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic
challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized
by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we
demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated
genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia
responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a
reduced fitness during hypoxic induction.
Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and
suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α overactivation.},
organization = {Junta de Andalucia

P10-CTS-0662
P12-CTS-38},
organization = {Spanish Ministry of Economy and Competitiveness 

SAF2012-40011-C02-01
SAF2015-70520- R
RTI2018-098968-B-I00
RTICC RD12/0036/0026},
organization = {CIBER Cancer ISCIII 

CB16/12/00421},
organization = {Basque Department of Industry, Tourism and Trade (Etortek)},
organization = {MINECO 

CB16/12/00421},
organization = {Fundacion Domingo Martinez},
publisher = {Elsevier},
keywords = {Hypoxia},
keywords = {PARP-1},
keywords = {PARylation},
keywords = {ChIP-seq},
keywords = {Tumor microenvironment},
title = {Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions},
doi = {10.1016/j.redox.2021.101885},
author = {Martí, Juan Manuel and García Díaz, Ángel and Delgado Bellido, Daniel and O'Valle Ravassa, Francisco Javier and González Flores, Ariannys and Oliver Pozo, Francisco Javier},
}