KDM5A and KDM5B histone-demethylases contribute to HU-induced replication stress response and tolerance

Author:

Gaillard Solenne1,Charasson Virginie1,Ribeyre Cyril2ORCID,Salifou Kader2,Pillaire Marie-Jeanne3,Hoffmann Jean-Sebastien4,Constantinou Angelos2,Trouche Didier1,Vandromme Marie1ORCID

Affiliation:

1. MCD, Centre de Biologie Integrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France

2. Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France

3. Cancer Research Center of Toulouse, INSERM U1037, CNRS ERL5294, University of Toulouse 3, 31037 Toulouse, France

4. Laboratoire de Pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 1 avenue Irène-Joliot-Curie, 31059 Toulouse cedex, France

Abstract

ABSTRACT KDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of ribonucleotide reductase. Second, they are required for optimal levels of activated Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. We also found that KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression.

Funder

Fondation TCS–INNABIOSANTE

Ligue Nationale contre le Cancer

Publisher

The Company of Biologists

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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