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

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.