Critical DNA damage recognition functions of XPC‐hHR23B and XPA‐RPA in nucleotide excision repair

Abstract

It has been reported that 80-90% of human cancers may result, in part, from DNA damage. Cell survival depends critically on the stability of our DNA and exquisitely sensitive DNA repair mechanisms have developed as a result. In humans, nucleotide excision repair (NER) protects the DNA against the mutagenic effects of carcinogens and ultraviolet (UV) radiation from sun exposure. By preventing mutations from forming in the DNA, the repair machinery ultimately protects us from developing cancers. DNA damage recognition is the rate-limiting step in repair, and although many details of NER have been elucidated, the mechanisms by which DNA damage is recognized remain to be fully determined. Two primary protein complexes have been proposed as the damaged DNA recognition factor in NER: xeroderma pigmentosum protein A-replication protein A (XPA-RPA) and xeroderma pigmentosum protein C-human homolog of RAD23B (XPC-hHR23B). Here we compare the evidence that supports damage detection by these protein complexes and propose a model for DNA damage recognition in NER based on the current understanding of the roles these proteins may play in the processing of DNA lesions.

The nucleotide excision repair pathway is required for UV-C-induced apoptosis in Caenorhabditis elegans

“…We posited that recognition of UV lesions by the NER machinery might be required not only for DNA repair, but also to activate the downstream signaling pathways that lead to apoptosis. To test this hypothesis, we analyzed the effect on UV-C-induced apoptosis of two previously uncharacterized mutations in the NER genes xpc-1(Y76B12C.2) and xpa-1, 28 which encode the C. elegans homologs of xeroderma pigmentosum complementation group C (XPC) and xeroderma pigmentosum complementation group A (XPA), respectively. Animals homozygous for the xpc-1(ok734) mutation showed reduced apoptosis following UV-C treatment, whereas their response to IR was normal (Figure 5a).…”

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

“…[3][4][5][6][7][8][9][10][11] It is now established that the first and rate-determining step in NER is the recognition of the bulky lesions by the XPC/HR23B protein heterodimer complex. 12 Since the NER machinery processes a diverse array of bulky lesions with different efficiencies, the conformational features that invoke NER are of great interest. Disturbed Watson-Crick pairing, impaired base stacking, and DNA bending are among the recognition hallmarks that have been proposed.…”

Epigenetic Silencing of the Human Nucleotide Excision Repair Gene, hHR23B, in Interleukin-6-responsive Multiple Myeloma KAS-6/1 Cells

“…The process of DNA repair is designed to maintain genomic integrity, which is continuously challenged by damaging factors such as reactive oxygen species generated by normal cellular metabolism, errors in DNA replication, ultraviolet radiation, and chemical reagents (1). Failure in the repair of DNA damage introduces genomic mutations, and long term accumulation of these mutations leads to genomic abnormalities as seen in many human cancers.…”

“…In mammalian cells, nucleotide excision repair (NER) 1 is one of the mechanisms for repairing DNA damage. The pivotal role of NER is to remove helix-distorting damage, including the UV-induced lesions (e.g.…”

“…[6 -4] photoproducts and cyclobutane pyrimidine dimers), interstrand and intrastrand cross-links, and chemically induced bulky DNA adducts. The NER process involves multistep mechanisms that require complexes of proteins to participate (1,2). Xeroderma pigmentosum is one of the inheritable diseases associated with an NER defect which confers UV hypersensitivity and skin carcinogenesis, suggesting that a reduced gene expression of NER proteins would result in failure to maintain genomic integrity (1,2).…”