Effect of the R406H Substitution on the Normal Function of CHEK2

Ahmet Yilmaz,Weiqiang Zhao,Michael E Davis

doi:10.4236/abb.2014.54046

Ahmet Yilmaz, Weiqiang Zhao + Show 1 more

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https://doi.org/10.4236/abb.2014.54046

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Abstract

CHEK2 (Checkpoint kinase homolog 2) encodes a protein involved in pathways that arrest the cell cycle in response to genomic stress such as DNA damage or replication blocks. Carriers of some of the CHEK2 mutations are at an increased risk of breast cancer. A mutation in the kinase domain of the CHEK2 gene resulting in the R406H substitution has been reported. However, it is currently unknown whether the substitution alters the function of CHEK2 in vitro. We evaluated the effect of the R406H substitution on the normal function of CHEK2 using a yeast complementation assay. The yeast cells lacking Rad53, the yeast homologue of human CHEK2 were transformed with the wild type as well as plasmids carrying mutations resulting in the R406H, 1100delC, and S428F variants. Yeast cells carrying the R406H variant grew at a rate similar to those carrying the wild type CHEK2, whereas the yeast carrying the S428F and 1100delC mutants grew at a slower rate. These results suggest that, unlike the well-known pathogenic alleles such as 1100delC and S428F, the R406H substitution does not abrogate the function of CHEK2. Therefore, this variant is probably not important in development of breast cancer in women.

Highlights

Comprising 31% of all cancers seen in women, breast cancer is one of the most common cancers [1]
Cells transformed with the R406H variant grew at a rate slightly lower than those carrying the wild type CHEK2 but higher than both of those carrying S428F or 1100delC variants
The results obtained in the current study are more in line with the observation that the 2% risk conferred by S428F is approximately half of the 5% risk conferred by the 1100delC variant in breast cancer patients with wild type BRCA1/2 [22]

Summary

Introduction

Comprising 31% of all cancers seen in women, breast cancer is one of the most common cancers [1]. Germline mutations in BRCA1/2 genes account for approximately 30% of inherited breast cancers [3]. The search for possible genetic causes of the remaining cases of inherited breast cancer without any mutation in BRCA1/2 has resulted in the discovery of rare germline mutations in several genes including CHEK2 (Checkpoint kinase homolog 2) [4]. CHEK2 encodes a protein that arrests the cell cycle in response to DNA damage. The halt in the cell cycle provides the cell with the time required for cellular repair of DNA, ensuring inheritance of only repaired or intact DNA [5]. The CHEK2 protein is divided into three distinct SQ/TQ, forkhead-associated, and serine/threonine kinase domains. The serine/threonine kinase domain is important in phosphorylating and activating target proteins

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