A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein

Ng, Jessica M.Y.; Vermeulen, Wim; Horst, Gijsbertus T. J. van der; Bergink, Steven; Sugasawa, Kaoru; Vrieling, Harry; Hoeijmakers, Jan H.J.

doi:10.1101/gad.260003

Cited by 232 publications

(233 citation statements)

References 51 publications

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“…XPC protein itself possesses DNA-binding activity, whereas the ubiquitin-binding Rad23B and the calcium-binding centrin-2 protect the initiator complex from degradation and stimulate its activity in DNA repair [28,30]. In double-mutant mouse cells lacking Rad23B as well as the functionally redundant Rad23A ortholog, XPC protein is completely degraded by proteasomal activity [31].…”

Section: Initiation Of Ggr Activity By the Xpc Complexmentioning

confidence: 99%

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

Clement

Camenisch

Jia

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Section: Initiation Of Ggr Activity By the Xpc Complexmentioning

confidence: 99%

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

Clement

Camenisch

Jia

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Rad23-family proteins can block extension of ubiquitin chains (Ortolan et al, 2000;Chen et al, 2001), and hHR23 proteins can block proteasome degradation of certain substrates (Hiyama et al, 1999;Raasi and Pickart, 2003). MEFs derived from targeted deletion of the mouse orthologs of hHR23 (mHR23A and B) demonstrated defects in xeroderma pigmentosa group-C (XP-C) protein stabilization, consistent with a role for mHR23 proteins in stabilizing specific proteasome substrates (Ng et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway

et al. 2004

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Abrogation of ubiquitin/proteasome-dependent turnover of p53 is critical for its activation. UbL-UBA proteins, including human homolog of Rad23 (hHR23) proteins, may regulate proteasomal degradation of substrates such as p53, due to their ability to interact with both ubiquitinated substrates and the proteasome. siRNAmediated depletion of hHR23A or hHR23B in human cell lines accelerated p53 degradation. In contrast, overexpression of hHR23 proteins led to the accumulation of ubiquitinated p53, and purified hHR23 proteins also blocked p53 proteasome degradation in vitro. An hHR23-MDM2 complex was identified, suggesting that MDM2 and hHR23 cooperate in the regulation of p53 proteasome degradation. Consistent with this hypothesis, an MDM2 mutant that demonstrated increased binding in vivo to hHR23A was able to ubiquitinate, but not degrade p53. Moreover, the defective phenotype of this MDM2 mutant was rescued by siRNA knockdown of hHR23A. Our data indicate that MDM2 acts at a step in the p53 degradation pathway after ubiquitination, to counteract hHR23 inhibition of p53 turnover. Moreover, our data suggest the possibility that ubiquitin ligase/UbL-UBA protein complexes, as exemplified by the MDM2/hHR23 complex, may serve a general role in regulating substrate degradation by the proteasome.

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“…The basic hypothesis in the field of NER is that the mammalian DNA repair apparatus recognizes structural distortions and thermodynamic destabilization in the DNA duplex caused by the lesions, followed by a verification step that detects the presence of a chemically modified nucleobase and the excision of a fragment 24-32 nucleotides long that contains the damaged base. [3][4][5][6][7][8][9][10][11] It is now established that the first and rate-determining step in NER is the recognition of the bulky lesions by the XPC/HR23B protein heterodimer complex. 12 Since the NER machinery processes a diverse array of bulky lesions with different efficiencies, the conformational features that invoke NER are of great interest.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

Cai

Patel

Geacintov

et al. 2007

Journal of Molecular Biology

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The nucleotide excision repair (NER) machinery excises a variety of bulky DNA lesions, but with varying efficiencies. The structural features of the DNA lesions that govern these differences are not well understood. An intriguing model system for studying structure-function relationships in NER is the major adduct derived from the reaction of the highly tumorigenic metabolite of benzo [a]pyrene, (+)-anti-benzo[a]pyrene diol epoxide, with the exocyclic amino group of guanine ((+)-trans-anti-[BP]-N 2 -dG, or G*). The rates of incision of the stereochemically identical lesions catalyzed by the prokaryotic UvrABC system was shown to be greater by a factor of 2.3±0.3 in the TG*T than in the CG*C sequence context [Biochemistry 46 (2007) 7006-7015]. Here we employ molecular dynamics simulations to elucidate the origin of the greater excision efficiency in the TG*T case and, more broadly, to delineate structural parameters that enhance NER. Our results show that the BP aromatic ring system is 5′-directed along the modified strand in the B-DNA minor groove in both sequence contexts. However, the TG*T modified duplex is much more dynamically flexible, featuring more perturbed and mobile Watson-Crick hydrogen bonding adjacent to the lesion, a greater impairment in stacking interactions, more dynamic local roll/ bending, and more minor groove flexibility. These characteristics explain a number of experimental observations concerning the (+)-trans-anti-[BP]-N 2 -dG adduct in double-stranded DNA with the TG*T sequence context: its conformational heterogeneity in NMR solution studies, its highly flexible bend, and its lower thermal stability. By contrast, the CG*C modified duplex is characterized by a single BP conformation and a rigid bend. While current recognition models of bulky lesions by NER factors have stressed the importance of impaired Watson-Crick pairing/ stacking and bending, our results highlight the likelihood of an important role for the local dynamics in the vicinity of the lesion.

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A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein

Cited by 232 publications

References 51 publications

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway

Dynamics of a Benzo[a]pyrene-derived Guanine DNA Lesion in TGT and CGC Sequence Contexts: Enhanced Mobility in TGT Explains Conformational Heterogeneity, Flexible Bending, and Greater Susceptibility to Nucleotide Excision Repair

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