Histona 1, o guardião da estabilidade genômica: mero acaso, fortuita necessidade ou design inteligente?

quinta-feira, agosto 31, 2017

Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin

Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués & Fernando Azorín

Nature Communications 8, Article number: 283 (2017)


Chromatin DNA damage and repair

Received: 29 January 2016 Accepted: 22 June 2017

Published online: 18 August 2017


Abstract

Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased γH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased γH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops). R-loops accumulation is readily detectable in G1-phase, whereas γH2Av increases mainly during DNA replication. These defects induce JNK-mediated apoptosis and are specific of dH1 depletion since they are not observed when heterochromatin silencing is relieved by HP1a depletion. Altogether, our results suggest that histone H1 prevents R-loops-induced DNA damage in heterochromatin and unveil its essential contribution to maintenance of genome stability.

Acknowledgements

We are thankful to Drs A. Casali, J. Casanova, O. Fernández-Capetillo, G. Fernández-Miranda, J.T. Kadonaga, R. Méndez, G. Roncador, T. Stracker and A. Vaquero for materials and advise. This work was supported by grants from MICINN (BFU2012-30724 and BFU2015-65082-P), the Generalitat de Catalunya (SGR2014-204) and by the European Community FEDER program. A.B.-F. and A.C.-L. acknowledge receipt of FPU (MED) and FPI (MINECO) fellowships, respectively.

Author information

Author notes

Aleix Bayona-Feliu

Present address: Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, 41092, Seville, Spain

Aleix Bayona-Feliu and Anna Casas-Lamesa contributed equally to this work.

Affiliations

Institute of Molecular Biology of Barcelona, IBMB, CSIC, Baldiri Reixac, 4, 08028, Barcelona, Spain

Aleix Bayona-Feliu, Anna Casas-Lamesa, Jordi Bernués & Fernando Azorín

Institute for Research in Biomedicine, IRB Barcelona, The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028, Barcelona, Spain

Aleix Bayona-Feliu, Anna Casas-Lamesa, Oscar Reina, Jordi Bernués & Fernando Azorín

Contributions

A.B.-F., A.C.-L. and J.B. performed the experiments. O.R. performed the Bioinformatics analyses. J.B. and F.A. designed the experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jordi Bernués or Fernando Azorín.