DNA Damage Recognition for Mammalian Global Genome Nucleotide Excision Repair

Sugasawa, Kaoru

doi:10.5772/23254

Cited by 3 publications

(2 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, when such lesions are located on the transcribed strand of active genes, transcription coupled NER (TC‐NER) will detect them via the lesion‐stalled transcription machinery (Hanawalt, 1994; Fousteri and Mullenders, 2008). In both cases, before incision of the damaged strand can take place (Oksenych and Coin, 2010), recruitment of TFIIH is indispensable for the opening of the double helix around the lesion and its subsequent verification together with XPA (Sugasawa, 2010). Interestingly, the CAK complex does not seem to be required for the GG‐NER reaction since it has been found to be released from TFIIH during GG‐NER (Coin et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

Generation of DNA single-strand displacement by compromised nucleotide excision repair

et al. 2012

View full text Add to dashboard Cite

Nucleotide excision repair (NER) is a precisely coordinated process essential to avoid DNA damage-induced cellular malfunction and mutagenesis. Here, we investigate the mechanistic details and effects of the NER machinery when it is compromised by a pathologically significant mutation in a subunit of the repair/transcription factor TFIIH, namely XPD. In contrast to previous studies, we find that no single-or double-strand DNA breaks are produced at early time points after UV irradiation of cells bearing a specific XPD mutation, despite the presence of a clear histone H2AX phosphorylation (cH2AX) signal in the UV-exposed areas. We show that the observed cH2AX signal can be explained by the presence of longer singlestrand gaps possibly generated by strand displacement. Our in vivo measurements also indicate a strongly reduced TFIIH-XPG binding that could promote single-strand displacement at the site of UV lesions. This finding not only highlights the crucial role of XPG's interactions with TFIIH for proper NER, but also sheds new light on how a faulty DNA repair process can induce extreme genomic instability in human patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Generation of DNA single-strand displacement by compromised nucleotide excision repair

et al. 2012

View full text Add to dashboard Cite

show abstract

“…A second part, comprising b-hairpin domains BHD2 and BHD3, interacts with a four-nucleotide segment of the undamaged strand opposing the lesion. Two of these undamaged nucleotides are displaced out of the double helix and accommodated into a handlike Rad4 protein fold, where the DNA adopts the configuration of a single-stranded overhang (38). The amino acids making contacts with these extrahelical nucleotides are evolutionarily conserved (Fig.…”

Section: Introductionmentioning

confidence: 99%

Dissection of the Xeroderma Pigmentosum Group C Protein Function by Site-Directed Mutagenesis

Clement

Kaczmarek

Mathieu

et al. 2011

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Xeroderma pigmentosum group C (XPC) protein is a sensor of helix-distorting DNA lesions, the function of which is to trigger the global genome repair (GGR) pathway. Previous studies demonstrated that XPC protein operates by detecting the single-stranded character of non-hydrogen-bonded bases opposing lesion sites. This mode of action is supported by structural analyses of the yeast Rad4 homologue that identified critical side chains making close contacts with a pair of extrahelical nucleotides. Here, alanine substitutions of the respective conserved residues (N754, F756, F797, F799) in human XPC were tested for DNA-binding activity, accumulation in tracks and foci of DNA lesions, nuclear protein mobility, and the induction of downstream GGR reactions. This study discloses a dynamic interplay between XPC protein and DNA, whereby the association with one displaced nucleotide in the undamaged strand mediates the initial encounter with lesion sites. The additional flipping-out of an adjacent nucleotide is necessary to hand over the damaged site to the next GGR player. Surprisingly, this mutagenesis analysis also reveals that the rapid intranuclear trafficking of XPC protein depends on constitutive interactions with native DNA, implying that the search for base damage takes place in living cells by a facilitated diffusion process. Xeroderma pigmentosum group C (XPC) protein is a sensor of helix-distorting DNA lesions, the function of which is to trigger the global genome repair (GGR) pathway. Previous studies demonstrated that XPC protein operates by detecting the single-stranded character of non-hydrogen-bonded bases opposing lesion sites. This mode of action is supported by structural analyses of the yeast Rad4 homologue that identified critical side chains making close contacts with a pair of extrahelical nucleotides. Here, alanine substitutions of the respective conserved residues (N754, F756, F797, F799) in human XPC were tested for DNA-binding activity, accumulation in tracks and foci of DNA lesions, nuclear protein mobility, and the induction of downstream GGR reactions. This study discloses a dynamic interplay between XPC protein and DNA, whereby the association with one displaced nucleotide in the undamaged strand mediates the initial encounter with lesion sites. The additional flipping-out of an adjacent nucleotide is necessary to hand over the damaged site to the next GGR player. Surprisingly, this mutagenesis analysis also reveals that the rapid intranuclear trafficking of XPC protein depends on constitutive interactions with native DNA, implying that the search for base damage takes place in living cells by a facilitated diffusion process.

show abstract

DNA Damage/Repair Management in Cancers

Alhmoud

Woolley

Moustafa

et al. 2020

Cancers

235

132

View full text Add to dashboard Cite

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways.

show abstract

DNA Damage Recognition for Mammalian Global Genome Nucleotide Excision Repair

Cited by 3 publications

References 111 publications

Generation of DNA single-strand displacement by compromised nucleotide excision repair

Generation of DNA single-strand displacement by compromised nucleotide excision repair

Dissection of the Xeroderma Pigmentosum Group C Protein Function by Site-Directed Mutagenesis

DNA Damage/Repair Management in Cancers

Contact Info

Product

Resources

About