Universität zu Köln

Milanese, Chiara ORCID: 0000-0001-8696-2603, Bombardieri, Cintia R., Sepe, Sara ORCID: 0000-0002-9884-9189, Barnhoorn, Sander, Payan-Gomez, Cesar ORCID: 0000-0002-0633-1332, Caruso, Donatella ORCID: 0000-0003-2115-778X, Audano, Matteo, Pedretti, Silvia, Vermeij, Wilbert P., Brandt, Renata M. C., Gyenis, Akos, Wamelink, Mirjam M., de Wit, Annelieke S., Janssens, Roel C., Leen, Rene, van Kuilenburg, Andre B. P., Mitro, Nico, Hoeijmakers, Jan H. J. and Mastroberardino, Pier G. (2019). DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Milanese, Chiara UNSPECIFIED orcid.org/0000-0001-8696-2603 UNSPECIFIED Bombardieri, Cintia R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sepe, Sara UNSPECIFIED orcid.org/0000-0002-9884-9189 UNSPECIFIED Barnhoorn, Sander UNSPECIFIED UNSPECIFIED UNSPECIFIED Payan-Gomez, Cesar UNSPECIFIED orcid.org/0000-0002-0633-1332 UNSPECIFIED Caruso, Donatella UNSPECIFIED orcid.org/0000-0003-2115-778X UNSPECIFIED Audano, Matteo UNSPECIFIED UNSPECIFIED UNSPECIFIED Pedretti, Silvia UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeij, Wilbert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandt, Renata M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gyenis, Akos UNSPECIFIED UNSPECIFIED UNSPECIFIED Wamelink, Mirjam M. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Wit, Annelieke S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Janssens, Roel C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leen, Rene UNSPECIFIED UNSPECIFIED UNSPECIFIED van Kuilenburg, Andre B. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitro, Nico UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mastroberardino, Pier G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-130360
DOI:	10.1038/s41467-019-12640-5
Journal or Publication Title:	Nat. Commun.
Volume:	10
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NUCLEOTIDE EXCISION-REPAIR; RNA-POLYMERASE-II; XERODERMA-PIGMENTOSUM; GENE-EXPRESSION; COMPLEMENTATION GROUP; ULTRAVIOLET-LIGHT; MOLECULAR-BIOLOGY; PROTEIN; CANCER; MECHANISMS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13036