Expanding molecular roles of UV-DDB: Shining light on genome stability and cancer

Abstract

UV-damaged DNA binding protein (UV-DDB) is a heterodimeric complex, composed of DDB1 and DDB2, and is involved in global genome nucleotide excision repair. Mutations in DDB2 are associated with xeroderma pigmentosum complementation group E. UV-DDB forms a ubiquitin E3 ligase complex with cullin-4A and RBX that helps to relax chromatin around UV-induced photoproducts through the ubiquitination of histone H2A. After providing a brief historical perspective on UV-DDB, we review our current knowledge of the structure and function of this intriguing repair protein. Finally, this article discusses emerging data suggesting that UV-DDB may have other non-canonical roles in base excision repair and the etiology of cancer. Introduction.Life has evolved a series of pathways to remove specific types of DNA damage. Nucleotide excision repair (NER) is dedicated to the removal of a wide variety of helix distorting lesions, including: ultraviolet (UV) photolesions, cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP); bulky adducts formed by chemical carcinogens, such as polycyclic aromatic hydrocarbons; and certain DNA lesions formed from chemotherapeutic agents, like cisplatin. NER consists of two sub-pathways: global genome NER (GG-NER) #

The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer

“…To this end our laboratory recently described a role for UV-damaged DNA binding protein (UV-DDB) in the BER of 8-oxoguanine [59]. UV-DDB is a heterodimeric protein, consisting of DDB1 and DDB2 subunits, and acts as first responder to UV-damage during nucleotide excision repair (NER) [60]. After UV-damage, UV-DDB forms an E3-ubiqutin ligase complex with Cul4A and RBX to ubiquitinate histones and remodel the chromatin to increase lesion accessibility for downstream repair proteins [61].…”

The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage

“…Moreover, the binding of UV-DDB seems to precede the activity of ATP-mediated chromatin remodelers ( 53 , 54 ). More recently, as discussed in the last section, our group has demonstrated that the oxidative base damage 8-oxoG, which only causes a mild helix distortion, is recognized by UV-DDB in naked duplex DNA, as well as in living cells ( 55 , 56 ). The relatively mild nucleosome distortion caused by CPD and 8-oxoG is analogous to cyPu.…”

“…It should be noted that previous studies missed that UV-DDB was able to discriminate between non-damaged DNA and DNA containing 8-oxoG ( 96 ). We have found that the presence of magnesium helps increase damage specificity by greatly decreasing binding to non-damaged DNA duplexes ( 55 , 56 ). EMSA assays conducted in the presence of 5 mM Mg 2+ showed that UV-DDB preferentially bound abasic sites, CPD and 8-oxoG, with equilibrium dissociation constants, K d , of 3.9, 30 and 160 nM, respectively, with high specificity as compared to undamaged DNA ( K d = 1108 nM) ( 55 , 56 ).…”

“…We have found that the presence of magnesium helps increase damage specificity by greatly decreasing binding to non-damaged DNA duplexes ( 55 , 56 ). EMSA assays conducted in the presence of 5 mM Mg 2+ showed that UV-DDB preferentially bound abasic sites, CPD and 8-oxoG, with equilibrium dissociation constants, K d , of 3.9, 30 and 160 nM, respectively, with high specificity as compared to undamaged DNA ( K d = 1108 nM) ( 55 , 56 ). Using an incision assay, with 8-oxoG and THF as substrates for OGG1 and APE1 specifically, we were able to show that UV-DDB increased the incision activity of both OGG1 and APE1 by 3- and 8-fold, respectively.…”

“…UV-damaged DNA binding protein (UV-DDB), a heterodimeric protein consisting of DDB1 and DDB2, has a demonstrated role in NER for damage recognition in the context of chromatin ( 95 ). In response to UV-induced damage, UV-DDB as part of a ubiquitin E3 ligase complex with Cul4A and RBX, ubiquitinates histone H2A to facilitate chromatin remodeling to increase lesion accessibility ( 55 ). UV-DDB is known to recognize and bind sites of UV damage, but has also been shown to bind more strongly to a short DNA duplex containing an abasic site, as compared to a DNA substrate containing a CPD, suggesting a possible role for UV-DDB in BER ( 96 , 97 ).…”