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

Biol Open. 2021 May 15;10(5):bio057729. doi: 10.1242/bio.057729. Epub 2021 May 26.

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.

Keywords: Chromatin; Drug tolerance; Replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Checkpoint Kinase 1 / metabolism
  • DNA Damage / drug effects*
  • DNA Repair
  • DNA Replication / drug effects*
  • Drug Tolerance* / genetics
  • Gene Expression Regulation
  • Histones / metabolism
  • Humans
  • Hydroxyurea / pharmacology*
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Retinoblastoma-Binding Protein 2 / genetics
  • Retinoblastoma-Binding Protein 2 / metabolism*
  • Ribonucleoside Diphosphate Reductase / genetics
  • Signal Transduction / drug effects

Substances

  • Histones
  • Nuclear Proteins
  • Repressor Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5A protein, human
  • KDM5B protein, human
  • Retinoblastoma-Binding Protein 2
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Hydroxyurea