Abstract
Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis.
Highlights
Xeroderma Pigmentosum is a rare autosomal hereditary disorder characterized by hypersensitivity to sunlight and predisposition to skin tumor development upon exposure to Ultraviolet light (UV) [1].The UV rays in sunlight causes variety of DNA damage lesions such as cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4 PPs)
Other models suggest that Cul4a-DDB1-Damaged DNA binding Protein-2 (DDB2) complex mono-ubiquitinates histones at the DNA damage site modulating the chromatin structure to help the repair factors gain access to the lesion
Later studies revealed that DDB2 deficient mouse embryonic fibroblasts or human carcinoma cells are resistant to most DNA damage (IR, chemotherapeutic drugs or E2F1) induced apoptosis [16]
Summary
Xeroderma Pigmentosum is a rare autosomal hereditary disorder characterized by hypersensitivity to sunlight and predisposition to skin tumor development upon exposure to Ultraviolet light (UV) [1]. The UV rays in sunlight causes variety of DNA damage lesions such as cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4 PPs) Cells constantly repair these damages to prevent accumulation. Xeroderma Pigmentosum is a genetic defect caused by mutations in the NER enzymes genes, leading to a deficiency in repair and high frequency skin carcinoma development upon UV exposure [3,4]. XPA through XPG encode proteins directly involved in NER Unlike these Xeroderma Pigmentosum variants, XP-V cells execute normal NER but are defective in the replication of UV damaged DNA. The XPE gene encodes Damaged DNA binding protein 2 (DDB2), smaller subunit of the damaged. XPE mutants are unable to bind to Cul4a suggesting role of Cul4a-DDB2 complex in NER [14]. The well-characterized targets of Cul4a-DDB1-DDB2 complex are XPC, p21 and DDB2 [15,16,17], which are all involved in the repair pathway further underscoring the importance of the protein ubiquitination activity of DDB2
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