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

## TL;DR

A rare genetic variant in the HELB gene disrupts its interaction with RPA, impairing DNA repair and potentially affecting the timing of menopause.

## Contribution

The study identifies a specific SNP in HELB that alters its function in DNA repair through reduced RPA interaction.

## Key findings

- The D506G substitution in HELB does not affect enzymatic activity on naked DNA but reduces unwinding on RPA-coated substrates.
- Impaired RPA interaction due to the D506G variant reduces HELB recruitment to DNA damage sites.
- Altered repair of meiotic DNA breaks may influence gamete viability and age at natural menopause.

## Abstract

HELB is a human helicase involved in initiation of DNA replication, the replication stress response, and regulation of double-strand DNA break repair. rs75770066 is a low-frequency single-nucleotide polymorphism (SNP) in the HELB gene that affects age at natural menopause (ANM). rs75770066 results in a D506G substitution in a HELB-specific motif in the 1A domain of the helicase that contains amino acids known to interact with RPA. We found that this amino acid change has no effect on the enzymatic activity of HELB on naked DNA substrates but reduces the rate of unwinding by HELB on RPA coated substrates, likely because D506G substitution in HELB reduces interaction with RPA. This impaired interaction of D506G HELB with RPA dramatically impairs the cellular function of HELB and likely results in the effects of rs75770066 as this reduces recruitment of HELB to sites of DNA damage. Reduced recruitment of D506G–HELB to double-strand DNA breaks and the concomitant increase in homologous recombination likely alters the levels of meiotic recombination, which affects the viability of gametes. Because menopause occurs when oocyte levels drop below a minimum threshold, altered repair of meiotic double-stranded DNA breaks has the potential to directly affect the ANM.

Graphical Abstract