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Cell cycle-dependent positive and negative functions of Fun30 chromatin remodeler in DNA damage response

Jasmine Siler1, Bowen Xia1, Carina Wong1

  • 1Department of Biology, University of Rochester, Rochester, NY 14627, USA.

DNA Repair
|January 17, 2017
PubMed

Insights

The Fun30 chromatin remodeler influences DNA damage response by regulating checkpoints and DNA resection. Its functions in genotoxin resistance, both positive and negative, are primarily active during the G2/M phase of the cell cycle.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The Fun30 chromatin remodeler is conserved across species and plays a role in DNA repair.
  • Fun30 is known to contribute to resistance against genotoxic agents like camptothecin (CPT), methyl methanesulfonate (MMS), and hydroxyurea (HU).
  • Its role in DNA double-strand break (DSB) resection is linked to CPT resistance, but its mechanisms for MMS and HU resistance are less understood.

Purpose of the Study:

  • To elucidate the mechanisms by which Fun30 confers resistance to genotoxic stress, particularly MMS and HU.
  • To investigate Fun30's role in regulating DNA damage checkpoints.
  • To determine the cell cycle-dependent functions of Fun30 in DNA damage response.

Main Methods:

  • Investigated Fun30's effect on Rad9-dependent and Rad9-independent DNA damage checkpoints.
  • Assessed Fun30's role in MMS and HU tolerance in the absence of the Rad5-dependent DNA damage tolerance pathway.
  • Analyzed Fun30's cell cycle regulation and expression patterns.
  • Manipulated Fun30 expression timing to assess its functional impact during specific cell cycle phases.

Main Results:

  • Fun30 downregulates the Rad9-dependent DNA damage checkpoint triggered by CPT or MMS.
  • Fun30 does not influence the Rad9-independent intra-S phase replication checkpoint induced by MMS or HU.
  • Fun30 exhibits a negative role in MMS and HU tolerance when the Rad5 pathway is absent, independent of checkpoint regulation.
  • Fun30 abundance peaks in the G2/M phase, and its functions in DNA damage response are primarily active during this phase.

Conclusions:

  • Fun30 contributes to DSB response by preventing excessive checkpoint activation and facilitating DNA resection.
  • Fun30's negative role in MMS/HU tolerance (without Rad5) is not linked to checkpoint control.
  • Both positive and negative functions of Fun30 in DNA damage response are predominantly executed in the G2/M phase of the cell cycle.
Keywords:
Cell cycle checkpointDNA damage responseDNA damage toleranceDNA replicationFun30Genotoxin

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