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

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. rs75770066 results in a D506G substitution in a HELB specific insertion 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 but dramatically impairs the cellular function of HELB. D506G HELB exhibits impaired interaction with RPA, which 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 age at natural menopause.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Alicia K. Byrd

PROVIDER: MSV000096390 | MassIVE | Tue Nov 12 07:15:00 GMT 2024

SECONDARY ACCESSION(S): PXD057796

REPOSITORIES: MassIVE

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