This entry includes caltractin (a calcium-binding protein found in the basal body complexes of algae such as Chlamydomonas) and centrin-2. Centrin-2 (CETN2, also known as caltractin isoform 1) is important for microtubule organization, centriole duplication and correct spindle formation. It is a calcium-binding protein with EF-hand binding sites []. It is a component of the XPC (xeroderma pigmentosum group C) and TREX-2 ((transcription and export complex 2)) complexes. The XPC complex recognizes damaged DNA which is required for global genome nucleotide excision repair []. Once XPC has interacted with unpaired bases on the undamaged DNA strand, the TFIH complex is recruited to find lesions on the opposite strand. The XPC complex is composed of XPC, RAD23B and CETN2 []. The TREX-2 complex helps dock export-competent ribonucleoprotein particles to the nuclear entrance of the nuclear pore complex []. The TREX-2 complex consists of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 [].
All proteins in this family for which functions are known are components of a multiprotein complex used for targeting nucleotide excision repair to specific parts of the genome. Rad23 contains a ubiquitin-like domain that interacts with catalytically active proteasomes and two ubiquitin(Ub)-associated (UBA) sequences that bind Ub. Rad23 interacts with ubiquitinated cellular proteins through thesynergistic action of its UBA domains. Inhumans, Rad23 complexes with the XPC protein.
The xeroderma pigmentosum C (XPC) protein has a central role in initiating global-genome NER (nucleotide excision repair) by recognising the lesion and recruiting downstream factors. This entry includes the yeast XPC orthologue Rad4 bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. Rad4 inserts a β-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 CPD-linked nucleotides become disordered. These findings indicate that the lesions recognised by Rad4/XPC thermodynamically destabilise the Watson-Crick double helix in a manner that facilitates the flipping-out of two base pairs [].This superfamily represents the β-hairpin domain BHD3 of the Rad4 protein, which is involved in DNA binding [].
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 [].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 β-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 []. Homologues of all the above mentioned yeast genes, except for RAD7, RAD16, and MMS19, have been identified in humans, and mutations in these human genesaffect 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 levelof UV sensitivity as do mutations in the other class 1 genes, and rad4 mutants are completely defective in incision. By contrast, XPC is required forthe repair of nontranscribed regions of the genome but not for the repair of the transcribed DNA strand.
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 [].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 β-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 []. Homologues of all the above mentioned yeast genes, except for RAD7, RAD16, and MMS19, have been identified in humans, and mutations in these human genesaffect 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 levelof UV sensitivity as do mutations in the other class 1 genes, and rad4 mutants are completely defective in incision. By contrast, XPC is required forthe repair of nontranscribed regions of the genome but not for the repair of the transcribed DNA strand.
