DNA repair protein Rad4 (IPR004583)
Short name: DNA_repair_Rad4
Overlapping homologous superfamilies
- DNA repair protein Rad4 (IPR004583)
- DNA repair protein Rad4, subgroup (IPR018026)
Mutations in the nucleotide excision repair (NER) pathway can cause the xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are limited to one DNA strand, but otherwise they are chemically and structurally diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet radiation. The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER by recognising the lesion and recruiting downstream factors.
In NER in eukaryotes, DNA is incised on both sides of the lesion, resulting in the removal of a fragment ~25-30 nucleotides long. This is followed by repair synthesis and ligation. This reaction, in yeast, requires the damage binding factors Rad14, RPA, and the Rad4-Rad23 complex, the transcription factor TFIIH which contains the two DNA helicases Rad3 and Rad25, essential for creating a bubble structure, and the two endonucleases, the Rad1-Rad10 complex and Rad2, which incise the damaged DNA strand on the 5'- and 3'-side of the lesion, respectively [PMID: 10915862].
The crystal structure of the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer lesion has been determined. The structure shows that Rad4 inserts a beta-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix. The expelled nucleotides of the undamaged strand are recognised by Rad4, whereas the two cyclobutane pyrimidine dimer-linked nucleotides become disordered. This indicates that the lesions recognised by Rad4/XPC thermodynamically destabilise the double helix in a manner that facilitates the flipping-out of two base pairs [PMID: 17882165].
Homologues of all the above mentioned yeast genes, except for RAD7, RAD16, and MMS19, have been identified in humans, and mutations in these human genes affect NER in a similar fashion as they do in yeast, with the exception of XPC, the human counterpart of yeast RAD4. Deletion of RAD4 causes the same high level of UV sensitivity as do mutations in the other class 1 genes, and rad4 mutants are completely defective in incision. By contrast, XPC is required for the repair of nontranscribed regions of the genome but not for the repair of the transcribed DNA strand.
- PTHR12135 (PTHR12135)