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Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair

Irene Kamileri1, Ismene Karakasilioti, Aria Sideri

  • 1Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece.

Proceedings of the National Academy of Sciences of the United States of America
|February 11, 2012
PubMed

Insights

Defects in nucleotide excision repair (NER) are linked to developmental disorders. The ERCC1-XPF endonuclease plays a novel role in transcription initiation, impacting mammalian development.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Nucleotide excision repair (NER) defects are implicated in various diseases, including developmental abnormalities, though the precise mechanisms are unclear.
  • The ERCC1-XPF endonuclease is a key component of the NER pathway, primarily known for DNA repair.

Purpose of the Study:

  • To investigate the role of the ERCC1-XPF endonuclease in mammalian development beyond DNA repair.
  • To elucidate the molecular mechanisms linking NER defects to developmental disorders.

Main Methods:

  • Utilized Ercc1(-/-) knockout mice to study physiological and gene expression changes.
  • Performed promoter occupancy studies, expression profiling, and in vitro differentiation assays.
  • Investigated interactions between ERCC1-XPF, TFIID, and RNA Polymerase II (POL II).

Main Results:

  • Ercc1(-/-) mice exhibit developmental parallels with transcription initiation defects (Taf10(-/-)).
  • ERCC1-XPF localizes to active promoters with the basal transcription machinery, including TFIID and POL II.
  • ERCC1-XPF is crucial for initial gene activation during development, not ongoing transcription.
  • ERCC1-XPF recruitment is associated with promoter-proximal DNA demethylation and active histone marks.

Conclusions:

  • The ERCC1-XPF endonuclease has a novel function in transcription initiation during mammalian development.
  • This role in transcription initiation establishes a direct link between ERCC1/XPF function and NER-associated developmental disorders.

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