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

Solenne Gaillard,Angelos Constantinou,Virginie Charasson,Cyril Ribeyre,Marie Vandromme,Kader Salifou,Didier Trouche,Marie-Jeanne Pillaire,Jean-Sebastien Hoffmann

doi:10.1242/bio.057729

Abstract

ABSTRACTKDM5A 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.

Highlights

KDM5 proteins belong to the JUMONJI family of demethylases that catalyse the removal of methyl groups from lysine residues on histone tails
KDM5A and KDM5B positively regulate RRM2 Because KDM5A or/and KDM5B are involved in the stable repression of E2F-dependent genes during differentiation and senescence (Chicas et al, 2012; van Oevelen et al, 2008), we asked if they regulate these genes in proliferative U2OS cells
In this study, we show that KDM5A and KDM5B proteins are involved in the management of replication stress (RS) induced by HU, by regulating the levels of RRM2, the regulatory subunit of the ribonucleotide reductase RNR, and of CHK1, an effector kinase of RS response

Summary

Introduction

KDM5 proteins belong to the JUMONJI family of demethylases that catalyse the removal of methyl groups from lysine residues on histone tails. KDM5 family proteins have been mainly described as transcriptional repressors They participate in multi-subunits co-repressor complexes containing histone deacetylase (HDAC) activity Received 6 November 2020; Accepted 20 April 2021 van Oevelen et al, 2008; Pasini et al, 2008; Tahiliani et al, 2007) They can function in some instances as co-activators. KDM5A and KDM5B bind to promoters of actively transcribed genes enriched in H3K4me (Beshiri et al, 2010; Liu and Secombe, 2015; Lopez-Bigas et al, 2008), meaning that their demethylase activity is tightly regulated, and that they function to recruit other regulators to chromatin (DiTacchio et al, 2011; Liu and Secombe, 2015; Nishibuchi et al, 2014; Secombe et al, 2007)

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