Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1
详细信息 查看全文
- 作者：Megan K. Brinkmeyer ; Sheila S. David ; ssdavid@ucdavis.edu" class="auth_mail" title="E-mail the corresponding author
- 关键词：9#3&minus ; 3#1 ; Rad9&ndash ; Hus1&ndash ; Rad1 ; araFA ; 9-(2-deoxy-2-fluoro-尾-d-arabinofuranosyl) adenine ; AST ; active site titration ; bp ; base-pair ; BER ; base excision repair ; CRC ; colorectal cancer ; ds ; double-stranded ; Ec ; Escherichia coli ; EMSA ; electrophoretic mobility shift assay ; FCL ; iron-sulfur cluster loop ; GFP ; green fluorescent protein ; IDC ; interdomain connector ; MAP ; MUTYH-associated polyposis ; MBP ; maltose-binding protein ; MOI ; multiplicity of infection ; PCNA ; proliferation cell nuclear
- 刊名：DNA Repair
- 出版年：2015
- 出版时间：October 2015
- 年：2015
- 卷：34
- 期：Complete
- 页码：39-51
- 全文大小：1758 K
文摘
- •
We provide a detailed analysis of the glycosylase activity and binding affinity of five MUTYH variants.
- •
A variant in the FCL motif of MUTYH (P281L) has minimal glycosylase activity due to an inability to bind to substrate DNA.
- •
R295C and R520Q MUTYH have low levels of active enzyme, exhibit compromised affinity for damaged DNA and reduced base excision catalysis.
- •
Q324H and P502L have nearly WT glycosylase activity, but exhibit reduced affinity for protein partners Hus1 (of the 9#3−3#1 complex) and PCNA, respectively.
- •
R520Q MUTYH also exhibits compromised affinity for PCNA suggesting a dual role for Arg 520 in OG:A mismatch recognition and interaction with PCNA.