The 8,5′-cyclopurine-2′-deoxynucleosides: Candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair

Abstract

It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other "bulky" chemical adducts are repaired by the nucleotide excision repair (NER) pathway. While this distinction is generally accurate, the 8,5'-cyclopurine deoxynucleosides represent an important exception, in that they are formed in DNA by the hydroxyl radical, but are specifically repaired by NER, not by BER. They are also strong blocks to nucleases and polymerases, including RNA polymerase II in human cells. In this review, I will discuss the evidence that these lesions are in part responsible for the neurodegeneration that occurs in some XP patients, and what additional evidence would be necessary to prove such a role. I will also consider other DNA lesions that might be involved in XP neurologic disease. Finally, I will also discuss how our recent studies of these lesions have generated novel insights into the process of transcriptional mutagenesis in human cells, as well as the value of studying these lesions not only for a better understanding of NER but also for other aspects of human health and disease.

Translesion Synthesis of 8,5′-Cyclopurine-2′-deoxynucleosides by DNA Polymerases η, ι, and ζ

“…Compared with E. coli cells, replicative bypass of S-cdG was more mutagenic in human 293T cells (ϳ50%), where we observed a higher frequency of G 3 T than the G 3 A mutation. The strong blocking and mutagenic effects of the cPu lesions on DNA replication in human cells, together with the abundant presence of these lesions in mammalian tissues (13,16,18,20,21), suggest that these lesions may constitute significant endogenous DNA lesions that may play important roles in the development of human diseases.…”

“…1). This additional covalent bond induces helical distortion to DNA and substantially stabilizes the glycosidic bond against acid-induced hydrolysis, which may prevent initiation of base excision repair by a DNA glycosylase and render the cPu lesions attractive substrates for nucleotide excision repair (13,21). Indeed, multiple lines of evidence supports that the cPu lesions are repaired by nucleotide excision repair, but not by base excision repair or direct enzymatic reversal (22)(23)(24)(25)(26).…”

“…These cPu lesions have been readily detected in vitro and in vivo under various conditions (13,(17)(18)(19). Moreover, it was recently shown that cPu lesions can accumulate in mammalian tissues in an age-dependent and tissue-specific manner, which may accelerate the natural processes of aging and contribute to the development of cancer, neurodegeneration, and other human diseases (13,16,18,20,21).…”

Relationship Between DNA Damage and Energy Metabolism: Evidence from DNA Repair Deficiency Syndromes

“…8,5'-cyclopurine-2'-deoxynucleaosides (cyPudNs) are endogenous lesions formed in DNA by the hydroxyl radical (Jaruga, Theruvathu, et al 2004;Dizdaroglu et al 1987). cyPudNs are chemically stable lesions which are expected to accumulate slowly and are candidates for lesions which could cause neurodegeneration (Kuraoka et al 2000;Brooks 2008). cyPudNs block transcription and, unlike most oxidative DNA lesions, cyPudNs are repaired by NER rather than BER (Brooks et al 2000;Kuraoka et al 2000).…”

The regulation of RNA Polymerase I-mediated transcription in forebrain neurons.

“…Genetic defects of several DNA repair pathways, including those for single-or double DNA strand breaks (SSBs or DSBs, respectively) as well as large chemical modifications of DNA bases that are also known as 'bulky' DNA ad ducts (Brooks, 2008;Caldecott, 2008;Katyal and McKinnon, 2008) provide a strong argument for a causative role of DNA damage in common neurodegenerative disorders. For instance, deficiencies of the DSB repair kinase ataxia telangiectasia-mutated protein kinase (ATM) trigger delayed neurodegeneration, presumably by blocking the developmental apoptosis of newly generated neurons harboring chromosomal abnormalities (Katyal and McKinnon, 2008).…”