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Predisposition to cancer caused by genetic and functional defects of mammalian Atad5

Daphne W Bell1, Nilabja Sikdar, Kyoo-Young Lee

  • 1Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America. belldaph@mail.nih.gov

Plos Genetics
|September 9, 2011
PubMed

Insights

Loss of ATAD5 function in mice causes genomic instability and high tumor incidence. Human ATAD5 mutations also link to endometrial tumors, suggesting ATAD5 suppresses cancer.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • ATAD5 is the human homolog of yeast Elg1 and is involved in PCNA deubiquitination.
  • PCNA modification is crucial for regulating DNA damage bypass pathways.
  • ATAD5's role in maintaining genomic stability in vivo is not well understood.

Purpose of the Study:

  • To investigate the in vivo function of ATAD5 in maintaining genomic stability.
  • To determine if ATAD5 deficiency leads to tumorigenesis in mammals.
  • To explore the clinical relevance of ATAD5 mutations in human cancers.

Main Methods:

  • Generation of heterozygous (Atad5(+/m)) mice with haploinsufficiency for Atad5.
  • Analysis of PCNA deubiquitination, DNA damage sensitivity, genomic instability, apoptosis, and aneuploidy in Atad5(+/m) mouse embryonic fibroblasts (MEFs).
  • Tumorigenesis assessment in Atad5(+/m) mice and analysis of somatic ATAD5 mutations in human endometrial tumors.

Main Results:

  • Atad5(+/m) mice exhibited significant genomic instability and hypersensitivity to DNA damage.
  • MEFs from Atad5(+/m) mice showed defects in PCNA deubiquitination and increased apoptosis and aneuploidy.
  • 90% of Atad5(+/m) mice developed various tumors, and human ATAD5 mutations were found in sporadic endometrial cancers.

Conclusions:

  • Mammalian Atad5 plays a critical role in suppressing genomic instability.
  • Loss-of-function mutations in ATAD5 are sufficient to cause tumorigenesis.
  • ATAD5 is a potential tumor suppressor, and its mutations are implicated in human endometrial cancer.

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