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

Solenne Gaillard1, Virginie Charasson1, Cyril Ribeyre2

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

Biology Open
|June 29, 2021
PubMed

Insights

KDM5A and KDM5B proteins manage replication stress (RS) by regulating RRM2 and Chk1. These demethylases are crucial for cancer cells to tolerate RS, impacting drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • KDM5A and KDM5B histone demethylases are overexpressed in various cancers.
  • These enzymes are implicated in cancer drug tolerance mechanisms.

Purpose of the Study:

  • To investigate the role of KDM5A and KDM5B in the cellular response to replication stress (RS).
  • To elucidate the mechanisms by which KDM5A/B contribute to RS tolerance.

Main Methods:

  • Analysis of KDM5A/B roles in regulating RRM2 and Chk1 activation.
  • Biochemical assays to determine KDM5A enrichment at replication forks and association with PCNA and Chk1.
  • Development and analysis of hydroxyurea (HU)-resistant cell models.

Main Results:

  • KDM5A and KDM5B positively regulate RRM2, the regulatory subunit of ribonucleotide reductase.
  • KDM5A/B are essential for optimal activated Chk1 levels, a key component of the intra-S phase checkpoint.
  • KDM5A localizes to replication forks and interacts with PCNA and Chk1.
  • KDM5A/B are required for RRM2 overexpression and HU resistance in tolerant cells.

Conclusions:

  • KDM5A/B are critical regulators of replication stress (RS) management.
  • Targeting KDM5 enzymatic activity may not fully address all cancer-related consequences of KDM5A/B overexpression.
Keywords:
ChromatinDrug toleranceReplication stress

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