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The spliceosome U2 snRNP factors promote genome stability through distinct mechanisms; transcription of repair

M Tanikawa1, K Sanjiv1, T Helleday1

  • 1Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Oncogenesis
|December 20, 2016
PubMed

Insights

Spliceosome U2 snRNP factors maintain DNA repair proteins and rapidly recruit to damage sites, revealing dual roles in genome stability and cancer. This highlights the complex interplay between splicing, transcription, and DNA damage response.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Recurrent mutations in spliceosome U2 small nuclear ribonucleoprotein complex (snRNP) components are found in malignancies.
  • Spliceosome factors are implicated in the DNA-damage response (DDR) and genome stability, emerging as hallmarks of cancer.
  • The precise role of the spliceosome in DNA repair remains largely unknown.

Purpose of the Study:

  • To elucidate the mechanisms by which spliceosome U2 snRNP factors contribute to genome stability.
  • To investigate the role of SNRPA1 in DNA repair and its recruitment dynamics.
  • To explore the interrelation between transcription, mRNA splicing, and the DDR.

Main Methods:

  • Whole-exome sequencing analysis of malignancies.
  • Genome-wide screens and proteomic analysis.
  • Real-time laser microirradiation assays.
  • Functional analysis of SNRPA1.

Main Results:

  • The spliceosome maintains protein levels of essential homologous recombination repair factors.
  • The U2 snRNP factor SNRPA1 is rapidly recruited to DNA-damage sites.
  • SNRPA1 plays a direct role in preventing R-loop-induced DNA damage.

Conclusions:

  • Spliceosome U2 snRNP factors contribute to genome stability through two distinct mechanisms: maintaining repair proteins and directly preventing DNA damage.
  • SNRPA1 has an immediate role in DNA repair, particularly in mitigating R-loop-associated damage.
  • Effective coping with genotoxic stress requires coordinated regulation of transcription, mRNA splicing, and DDR.

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