The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the f...

Full description

Saved in:
Bibliographic Details
Published in:International journal of molecular sciences 2024-02, Vol.25 (3), p.1664
Main Authors: Atkinson, Caroline, McInerney-Leo, Aideen M, Proctor, Martina, Lanagan, Catherine, Stevenson, Alexander J, Dehkhoda, Farhad, Caole, Mary, Maas, Ellie, Ainger, Stephen, Pritchard, Antonia L, Johansson, Peter A, Leo, Paul, Hayward, Nicholas K, Sturm, Richard A, Duncan, Emma L, Gabrielli, Brian
Format: Article
Language:English
Subjects:
Ataxia
Cancer
Cell cycle
CRISPR
DNA damage
DNA repair
Ethylenediaminetetraacetic acid
Genetic aspects
Genomics
Medical research
Medicine, Experimental
Melanoma
Phosphorylation
Protein kinases
Proteins
Radiation
Senescence
Tumor proteins
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25031664