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Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

Meichun Xing1, Xiaohui Wang1, Timea Palmai-Pallag2

  • 1Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.

Oncotarget
|September 29, 2015
PubMed

Insights

The MUS81 nuclease is crucial for maintaining DNA replication fork integrity in human cells. Its depletion causes DNA damage, senescence, and impaired replication recovery, highlighting its essential role.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • MUS81 is a conserved DNA structure-specific nuclease involved in DNA replication and repair.
  • While Mus81 gene inactivation shows minimal embryonic effects in mice, cancer susceptibility is noted.

Purpose of the Study:

  • To investigate the essential roles of the MUS81 nuclease in human cells.
  • To understand the consequences of MUS81 depletion on DNA replication and damage response.

Main Methods:

  • Acute depletion of MUS81 protein using short hairpin RNAs (shRNAs) in human fibroblasts.
  • Analysis of single-stranded DNA (ssDNA) accumulation, DNA damage response, and cellular senescence.
  • Assessment of replication fork progression and recovery after stalling.

Main Results:

  • MUS81 depletion leads to significant ssDNA accumulation and a constitutive DNA damage response.
  • Depletion activates cellular senescence, indicating a role in preventing genomic instability.
  • MUS81 is essential for efficient replication fork progression and recovery from replication stress.

Conclusions:

  • The MUS81 nuclease plays a critical role in maintaining replication fork integrity in human cells.
  • MUS81 is vital for preventing DNA damage accumulation and promoting cell survival during replication stress.
Keywords:
DNA replicationHolliday junctionsNBS1cellular senescencehomologous recombination

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