Tautomerization-dependent recognition and excision of oxidation damage in base-excision DNA repair.
نویسندگان
چکیده
NEIL1 (Nei-like 1) is a DNA repair glycosylase guarding the mammalian genome against oxidized DNA bases. As the first enzymes in the base-excision repair pathway, glycosylases must recognize the cognate substrates and catalyze their excision. Here we present crystal structures of human NEIL1 bound to a range of duplex DNA. Together with computational and biochemical analyses, our results suggest that NEIL1 promotes tautomerization of thymine glycol (Tg)-a preferred substrate-for optimal binding in its active site. Moreover, this tautomerization event also facilitates NEIL1-catalyzed Tg excision. To our knowledge, the present example represents the first documented case of enzyme-promoted tautomerization for efficient substrate recognition and catalysis in an enzyme-catalyzed reaction.
منابع مشابه
p53 and regulation of DNA damage recognition during nucleotide excision repair.
In response to a variety of types of DNA damage, the p53 tumor suppressor gene product is activated and regulates a number of downstream cellular processes such as cell cycle arrest, apoptosis and DNA repair. Recent discoveries concerning the regulation of DNA repair processes by p53, such as nucleotide excision repair (NER) and base excision repair (BER) have paved the way for studies to under...
متن کاملDNA Base Excision Repair: Evolving Biomarkers for Personalized Therapies in Cancer
DNA repair is critical for maintaining genomic integrity. The DNA damage such as those induced by endogenous processes (methylation, hydroxylation, oxidation by free radicals) or by exogenous agents such as ionizing radiation, environmental toxins, and chemotherapy is processed through the DNA repair machinery in cells. At least six distinct DNA repair pathways have been described. A detailed d...
متن کاملDNA Repair Pathways and Mechanisms
Our cells are constantly exposed to insults from endogenous and exogenous agents that can introduce damage into our DNA and generate genomic instability. Many of these lesions cause structural damage to DNA and can alter or eliminate fundamental cellular processes, such as DNA replication or transcription. DNA lesions commonly include base and sugar modifications, singleand double-strand breaks...
متن کاملATP-stimulated, DNA-mediated redox signaling by XPD, a DNA repair and transcription helicase.
Using DNA-modified electrodes, we show DNA-mediated signaling by XPD, a helicase that contains a [4Fe-4S] cluster and is critical for nucleotide excision repair and transcription. The DNA-mediated redox signal resembles that of base excision repair proteins, with a DNA-bound redox potential of ~80 mV versus NHE. Significantly, this signal increases with ATP hydrolysis. Moreover, the redox signa...
متن کاملChk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair.
The DNA damage response (DDR) has an essential function in maintaining genomic stability. Ataxia telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2) and ATM- and Rad3-related (ATR)-Chk1, triggered, respectively, by DNA double-strand breaks and blocked replication forks, are two major DDRs processing structurally complicated DNA damage. In contrast, damage repaired by base excision repair (B...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 113 28 شماره
صفحات -
تاریخ انتشار 2016