Nucleotide Excision Repair and Related Human Diseases

Abstract

Nucleotide excision repair (NER) of DNA-lesions is the most versatile DNA repair mechanism involved in genome maintenance, cell and organismal preservation. Deciphering the stepwise mechanism of NER has mostly relied on cells from rare patients presenting photosensitive, recessively inherited genetic disorders such as xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne (CS) syndromes. Cells from these patients share various extents of impaired capacity of repairing UV-induced DNA lesions (cyclobutane pyrimidine dimers, 6-4 pyrimidine-pyrimidone photo products) located either in transcribed DNA strands or in inactive DNA. We review here the essentials of NER actors and how impairment of their activity may lead to distinct and characteristic human disorders whose presentation may be limited to developmental trait (TTD; CS), or cumulate with cancer susceptibility toward genotoxic aggressions, most notably short wavelength ultraviolets.

Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back

“…Mutations in the xeroderma pigmentosum group B protein (XPB), XPD, and p8 subunits of TFIIH are associated with various human diseases, including cancer [79]. The Dmp52 subunit of TFIIH in Drosophila has been shown to directly interact with the fly homolog of p53 (Dp53).…”

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

“…A particularly relevant issue related to TFIIH is its association with human diseases: mutations in its XPB, XPD and p8 subunits are linked to xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy and cancer (Bergoglio and Magnaldo, 2006). Mutations in other subunits of TFIIH associated with syndromes have not yet been reported in humans.…”

The Ubiquitin-Proteasome System and DNA Repair

“…Upon removal of this fragment, the resulting ~30 nucleotide gap is filled by DNA polymerases and in a PCNA-dependent manner, and a DNA ligase covalently attaches the 3' end of the newly synthesized strand to the flanking DNA (Lommel et al, 2000). Defects in NER are associated with diseases such as Xeroderma Pigmentosum, Cockayne's Syndrome, and Trichothiodystrophy (Bergoglio & Magnaldo, 2006;Leibeling et al, 2006).…”