Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Bart, François; Angers, Jean-Philippe; Fortier, Emile; Hammond-Martel, Ian; Costantino, Santiago; Drobetsky, Elliot; Würtele, Hugo

doi:10.1074/jbc.m115.685883

Cited by 23 publications

(45 citation statements)

References 53 publications

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“…Consistent with this notion, several recent studies have suggested that “RPA exhaustion” is a frequent problem in cells undergoing extensive replicative stress [134,148–151], including following UV exposure. Thus, it is possible that an insufficient supply of RPA in keratinocytes stressed by IGF-1R inactivation may lower the pool of RPA available for NER and ATR-CHK1 signaling.…”

Section: Effect Of Aging On Insulin-like Growth Factor-1 (Igf-1) Pmentioning

confidence: 79%

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

2017

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The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.

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Section: Effect Of Aging On Insulin-like Growth Factor-1 (Igf-1) Pmentioning

confidence: 79%

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

2017

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“…DNA was quantified with PicoGreen (ThermoFisher) using a TBS-380 fluorimeter (Turner Biosystems). Note that 100 ng of DNA was analyzed by slot blotting with rat anti-cisplatinmodified DNA antibody (Abcam, ab103261) as described (18).…”

Section: Quantification Of Cddp-induced Dna Adductsmentioning

confidence: 99%

“…Images were acquired using a DeltaVision Elite system (GE Healthcare). Intensity of nuclear RPA2 signals was evaluated using custom software, as described (18). At least 200 cells combined from 2 independent experiments were quantified for each condition.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

“…Defective responses to replication stress often lead to excessive recruitment of RPA at stalled RF (17,18). We measured chromatin-bound RPA at 3 hours post-UV in 3 SPRand 3 SPR þ HGSOC lines using immunofluorescence microscopy.…”

Section: Spr-deficient Cddp-sensitive Hgsoc Cell Lines Exhibit Abnormmentioning

confidence: 99%

“…Under conditions of limited RPA availability, important RPAdependent processes aside from DNA replication can be compromised, which might contribute to increased RF stalling/failure. Indeed, we and others have shown, in various mutant yeast strains and mammalian cell lines exhibiting replication stress response defects, that sequestration of RPA at stalled RF exhausts the cellular pools of this complex, thus interfering with its ability to perform essential functions in NER during S phase (17,18). Moreover, we previously demonstrated that a majority of human melanoma cell lines exhibit striking defects in NER exclusively during S, although the molecular basis was not thoroughly investigated (19).…”

Section: Introductionmentioning

confidence: 96%

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Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells

et al. 2018

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Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNA crosslinks that block replicative DNA polymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPA-dependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here, we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, RF instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines. The influence of replication protein A exhaustion on cisplatin sensitivity harbors important implications toward improving therapy of various cancers that initially respond to platinum-based agents but later relapse due to intrinsic or acquired drug resistance. .

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Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

Khan

Travers

Kemp

2018

Environ and Mol Mutagen

106

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The growing incidence of melanoma is a serious public health issue that merits a thorough understanding of potential causative risk factors, which includes exposure to ultraviolet radiation (UVR). Though UVR has been classified as a complete carcinogen and has long been recognized for its ability to damage genomic DNA through both direct and indirect means, the precise mechanisms by which the UVA and UVB components of UVR contribute to the pathogenesis of melanoma have not been clearly defined. In this review, we therefore highlight recent studies that have addressed roles for UVA radiation in the generation of DNA damage and in modulating the subsequent cellular responses to DNA damage in melanocytes, which are the cell type that gives rise to melanoma. Recent research suggests that UVA not only contributes to the direct formation of DNA lesions but also impairs the removal of UV photoproducts from genomic DNA through oxidation and damage to DNA repair proteins. Moreover, the melanocyte microenvironment within the epidermis of the skin is also expected to impact melanomagenesis, and we therefore discuss several paracrine signaling pathways that have been shown to impact the DNA damage response in UV-irradiated melanocytes. Lastly, we examine how alterations to the immune microenvironment by UVA-associated DNA damage responses may contribute to melanoma development. Thus, there appear to be multiple avenues by which UVA may elevate the risk of melanoma. Protective strategies against excess exposure to UVA wavelengths of light therefore have the potential to decrease the incidence of melanoma. Environ. Mol. Mutagen. 59:438-460, 2018. © 2018 Wiley Periodicals, Inc.

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Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair

Cited by 23 publications

References 53 publications

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells

Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

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