Abstract
Trinucleotide repeat (TNR) instability is associated with human neurodegenerative diseases and cancer. Recent studies have pointed out that DNA base excision repair (BER) mediated by DNA polymerase β (pol β) plays a crucial role in governing somatic TNR instability in a damage-location dependent manner. It has been shown that the activities and function of BER enzymes and cofactors can be modulated by their polymorphic variations. This could alter the function of BER in regulating TNR instability. However, the roles of BER polymorphism in modulating TNR instability remain to be elucidated. A previous study has shown that a pol β polymorphic variant, polβR137Q is associated with cancer due to its impaired polymerase activity and its deficiency in interacting with a BER cofactor, proliferating cell nuclear antigen (PCNA). In this study, we have studied the effect of the pol βR137Q variant on TNR instability. We showed that pol βR137Q exhibited weak DNA synthesis activity to cause TNR deletion during BER. We demonstrated that similar to wild-type pol β, the weak DNA synthesis activity of pol βR137Q allowed it to skip over a small loop formed on the template strand, thereby facilitating TNR deletion during BER. Our results further suggest that carriers with pol βR137Q polymorphic variant may not exhibit an elevated risk of developing human diseases that are associated with TNR instability.
Highlights
Human genome is susceptible to a variety of types of DNA damage that can modify DNA bases, deoxyribose sugar phosphate groups as well as directly break DNA backbone [1]
Typically microsatellite instability is responsible for many human diseases [9,10,11,12] including GT repeat instability that is associated with colon cancer [13] as well as trinucleotide repeat (TNR) expansion diseases [14,15,16,17].TNR expansion has been identified as the cause of more than 40 neurodegenerative diseases [14, 18] including Huntington’s disease (HD), spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 17 and spinal bulbar muscular atrophy (SBMA) (Kennedy’s disease) (CAG repeat expansion) [17, 19, 20], myotonic dystrophy type 1 (DM1) (CTG repeat expansion), Friedreich’s ataxia (GAA repeat expansion) and fragile X syndrome (CGG repeat expansion) [21,22,23]
With the damage located in the middle of the (CTG)20 substrate, 1 nM and 2.5 nM pol βR137Q variant inserted 2 nucleotides and 1 repeat, respectively (Fig 1D, lanes 14–15), whereas the wildtype pol β at the same concentrations inserted 1 nucleotide and up to 2 repeats, respectively (Fig 1D, lanes 11–12)
Summary
Human genome is susceptible to a variety of types of DNA damage that can modify DNA bases, deoxyribose sugar phosphate (dRP) groups as well as directly break DNA backbone [1]. Typically microsatellite instability is responsible for many human diseases [9,10,11,12] including GT repeat instability that is associated with colon cancer [13] as well as trinucleotide repeat (TNR) expansion diseases [14,15,16,17].TNR expansion has been identified as the cause of more than 40 neurodegenerative diseases [14, 18] including Huntington’s disease (HD), spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 17 and spinal bulbar muscular atrophy (SBMA) (Kennedy’s disease) (CAG repeat expansion) [17, 19, 20], myotonic dystrophy type 1 (DM1) (CTG repeat expansion), Friedreich’s ataxia (GAA repeat expansion) and fragile X syndrome (CGG repeat expansion) [21,22,23]. CAG repeat deletion in the androgen receptor (AR) gene can result in a high transcriptional activity of the AR protein [26,27,28], which may potentially lead to progression of prostate cancer [29, 30]
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