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Rare SNP in the HELB gene interferes with RPA interaction and cellular function of HELB

Bertha Osei1, Benjamin H May1, Clara M Stiefel1

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.

Biorxiv : the Preprint Server for Biology
|March 11, 2024
PubMed

Insights

A rare genetic variant in the HELB gene (rs75770066) impairs DNA repair, potentially affecting gamete viability and influencing the age at natural menopause.

Area of Science:

  • Genetics
  • Molecular Biology
  • Reproductive Biology

Background:

  • HELB is a crucial human helicase regulating DNA replication, replication stress response, and DNA double-strand break repair.
  • A rare single nucleotide polymorphism (SNP), rs75770066, in the HELB gene is associated with age at natural menopause.

Purpose of the Study:

  • To investigate the functional impact of the rs75770066 SNP on HELB protein function and its potential link to the age at natural menopause.

Main Methods:

  • Analyzing the effect of the D506G amino acid substitution (caused by rs75770066) on HELB's interaction with RPA.
  • Assessing HELB recruitment to DNA damage sites and its role in homologous recombination repair.
  • Correlating altered DNA repair mechanisms with gamete viability and age at menopause.

Main Results:

  • The D506G substitution in HELB significantly impairs its cellular function and interaction with RPA.
  • This impairment reduces HELB recruitment to DNA damage sites, leading to increased homologous recombination.
  • Altered repair of meiotic double-strand DNA breaks potentially affects gamete viability and consequently, the age at natural menopause.

Conclusions:

  • The rs75770066 variant in HELB disrupts DNA repair pathways, impacting reproductive processes.
  • This genetic variation provides a molecular link between DNA repair efficiency and the timing of natural menopause.

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