p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

Laposa, Rebecca R.; Feeney, Luzviminda; Crowley, Eileen; Feraudy, Sébastien de; Cleaver, James E.

doi:10.1016/j.dnarep.2007.07.005

Cited by 11 publications

(7 citation statements)

References 58 publications

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“…Because loss of p53 sensitizes normal fibroblasts, but not XPV cells, to UV (53,54), we hypothesized that the UV protection conferred by Polη is mediated by p53. To test this hypothesis, we compared UV survival in p53-depleted HDF cells infected with ‘empty’ control adenovirus or adenovirus expressing Polη at levels that confer UV survival in XPV fibroblasts (Supplementary Figure S6).…”

Section: Resultsmentioning

confidence: 99%

A non-catalytic role of DNA polymerase η in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks

Durando

Tateishi

Vaziri

2013

Nucleic Acids Research

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Trans-lesion DNA synthesis (TLS) is a DNA damage-tolerance mechanism that uses low-fidelity DNA polymerases to replicate damaged DNA. The inherited cancer-propensity syndrome xeroderma pigmentosum variant (XPV) results from error-prone TLS of UV-damaged DNA. TLS is initiated when the Rad6/Rad18 complex monoubiquitinates proliferating cell nuclear antigen (PCNA), but the basis for recruitment of Rad18 to PCNA is not completely understood. Here, we show that Rad18 is targeted to PCNA by DNA polymerase eta (Polη), the XPV gene product that is mutated in XPV patients. The C-terminal domain of Polη binds to both Rad18 and PCNA and promotes PCNA monoubiquitination, a function unique to Polη among Y-family TLS polymerases and dissociable from its catalytic activity. Importantly, XPV cells expressing full-length catalytically-inactive Polη exhibit increased recruitment of other error-prone TLS polymerases (Polκ and Polι) after UV irradiation. These results define a novel non-catalytic role for Polη in promoting PCNA monoubiquitination and provide a new potential mechanism for mutagenesis and genome instability in XPV individuals.

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Section: Resultsmentioning

confidence: 99%

A non-catalytic role of DNA polymerase η in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks

Durando

Tateishi

Vaziri

2013

Nucleic Acids Research

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“…13,26 Indeed, genomic instability is significantly greater in tumors with mutated p53 compared with wild-type tumors (Ridd K., unpublished data), as also occurs in cell cultures after inactivation of p53 by shRNA or SV40 transformation. 29 XPC is regulated by p53 at the transcriptional level, and expression of wild-type p53 is required for nucleotide excision repair. 30,31 However, we found no correlation between p53 and XPC expression by IHC (Table 3).…”

Section: Discussionmentioning

confidence: 99%

The DNA Damage-Binding Protein XPC Is a Frequent Target for Inactivation in Squamous Cell Carcinomas

Feraudy

Ridd

Richards

et al. 2010

The American Journal of Pathology

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XPC, the main damage-recognition protein responsible for nucleotide excision repair of UVB damage to DNA, is lost or mutated in xeroderma pigmentosum group C (XP-C), a rare inherited disease characterized by high incidence and early onset of non-melanoma and melanoma skin cancers. The high incidence of skin cancers in XP-C patients suggests that loss of expression of XPC protein might also provide a selective advantage for initiation and progression of similar cancers in non XP-C patients in the general population. To test whether XPC is selectively lost in squamous cell carcinomas from non XP-C patients, we examined XPC expression by immunohistochemistry on a tissue microarray with 244 tissue cores, including in situ and invasive squamous-cell carcinomas (SCCs), keratoacanthoma (KA), and normal skin samples from both immunocompetent and immunosuppressed patients. We found that XPC expression was lost in 49% of invasive squamous cell carcinomas from immunocompetent patients and 59% from immunosuppressed patients. Loss of expression was correlated with deletions of chromosomal 3p and mutations in the XPC gene. The XPC gene is consequently inactivated or lost in almost half of squamous cell carcinomas from non XP-C patients. Loss or mutation of XPC may be an early event during skin carcinogenesis that provides a selective advantage for initiation and progression of squamous cell carcinomas in

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“…ATR depletion increases pan-nuclear and S-phase cH2AX after low doses of UVB irradiation in XP-C and XP-V cells Replication arrest after UVC irradiation induces the phosphorylation of H2AX (denoted cH2AX), and this phosphorylation is further increased in SV40-immortalized cells, especially in XP-V cells (Laposa et al, 2007;Limoli et al, 2002). Given the role of ATR in the replication fork and in the induction of caspase-3 activity during S-phase, we quantified the level of cH2AX after UVB irradiation to evaluate whether sensitivity was related to replication stress.…”

Section: Atr-depleted Sv40-immortalized Fibroblasts Are Hypersensitivmentioning

confidence: 99%

ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways

Andrade-Lima

Andrade

Menck

2014

Journal of Cell Science

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Ultraviolet (UV) light can stall replication forks owing to the formation of bulky lesions in the DNA. Replication across these blocking lesions occurs through translesion DNA synthesis, and cells activate the ATR damage responses to UV. However, it remains unclear whether lesion bypass requires the replication checkpoint because ATR is not necessary for PCNA ubiquitylation. We observed that ATR knockdown by siRNA increased replication stress and promoted early induction of apoptosis following UVB irradiation in SV40-immortalized human cells, including cells from XP-V and XP-C patients. XP-V cells were further sensitized by the silencing, indicating that DNA polymerase g (Pol g) remains active despite ATR control. However, following UVB irradiation, ATR-depleted cells were unable to achieve mitosis, as would be expected after the loss of a DNA checkpoint control. Thus, ATR also regulates replication arrest recovery following UVB-induced damage, independently of Pol g, in SV40-immortalized cell lines. The ATR-mediated DNA damage response regulates replication and different tolerance pathways, and in these cells, ATR depletion induces replication catastrophe, which contributes to explain the potential of ATR inhibition to protect against UVB-induced carcinogenesis.

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p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

Cited by 11 publications

References 58 publications

A non-catalytic role of DNA polymerase η in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks

A non-catalytic role of DNA polymerase η in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks

The DNA Damage-Binding Protein XPC Is a Frequent Target for Inactivation in Squamous Cell Carcinomas

ATR suppresses apoptosis after UVB light by controlling both translesion synthesis and alternative tolerance pathways

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