DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Mogi, Seiki; Butcher, Christina E.; Oh, Dennis H.

doi:10.1016/j.yexcr.2007.10.031

Cited by 31 publications

(30 citation statements)

References 47 publications

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“…For example, XP-V cells are sensitive to cisplatin, suggesting that bypass of cisplatin lesions may depend on Pol (1). Combined NER-and Pol -mediated lesion bypass has also been suggested as the likely mechanism for repairing DNA interstrand cross-links formed by mitomycin C (46) and psoralen (32). In contrast, Pol does not appear to play a role in replication past endogenous lesions such as 8-oxoguanine (3) or abasic sites (2).…”

mentioning

confidence: 99%

Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

Rey

Sidorova²,

Puget

et al. 2009

Molecular and Cellular Biology

107

101

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Human DNA polymerase (Pol ) modulates susceptibility to skin cancer by promoting translesion DNA synthesis (TLS) past sunlight-induced cyclobutane pyrimidine dimers. Despite its well-established role in TLS synthesis, the role of Pol in maintaining genome stability in the absence of external DNA damage has not been well explored. We show here that short hairpin RNA-mediated depletion of Pol from undamaged human cells affects cell cycle progression and the rate of cell proliferation and results in increased spontaneous chromosome breaks and common fragile site expression with the activation of ATM-mediated DNA damage checkpoint signaling. These phenotypes were also observed in association with modified replication factory dynamics during S phase. In contrast to that seen in Pol -depleted cells, none of these cellular or karyotypic defects were observed in cells depleted for Pol , the closest relative of Pol . Our results identify a new role for Pol in maintaining genomic stability during unperturbed S phase and challenge the idea that the sole functional role of Pol in human cells is in TLS DNA damage tolerance and/or repair pathways following exogenous DNA damage.

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mentioning

confidence: 99%

Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

Rey

Sidorova²,

Puget

et al. 2009

Molecular and Cellular Biology

107

101

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“…In these experiments, using xeroderma pigmentosum patient-derived XPV cells, partial requirement for PolH was observed (42). Moreover, XPV cells are hypersensitive to cisplatin (43,44), and PolH was associated with processing of psoralen-induced crosslinks (45).…”

Section: Discussionmentioning

confidence: 91%

Translesion Polymerase η Is Upregulated by Cancer Therapeutics and Confers Anticancer Drug Resistance

et al. 2014

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DNA repair processes are a key determinant of the sensitivity of cancer cells to DNA-damaging chemotherapeutics, which may induce certain repair genes as a mechanism to promote resistance. Here, we report the results of a screen for repair genes induced in cancer cells treated with DNA crosslinking agents, which identified the translesion polymerase h (PolH) as a p53-regulated target acting as one defense against interstrand crosslink (ICL)-inducing agents. PolH was induced by fotemustine, mafosfamide, and lomustine in breast cancer, glioma, and melanoma cells in vitro and in vivo, with similar inductions observed in normal cells such as lymphocytes and diploid fibroblasts. PolH contributions to the protection against ICL-inducing agents were evaluated by its siRNAmediated attenuation in cells, which elevated sensitivity to these drugs in all tumor cell models. Conversely, PolH overexpression protected cancer cells against these drugs. PolH attenuation reduced repair of ICL lesions as measured by host cell reactivation assays and enhanced persistence of gH2AX foci. Moreover, we observed a strong accumulation of PolH in the nucleus of drug-treated cells along with direct binding to damaged DNA. Taken together, our findings implicated PolH in ICL repair as a mechanism of cancer drug resistance and normal tissue protection. Cancer Res; 74(19); 5585-96. Ó2014 AACR.

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“…It has been shown that photoactivated psoralen (PUVA) can induce p53, ␥H2AX, and cell-cycle arrest and apoptosis (Mogi et al, 2008;Viola et al, 2008). The precise mechanism by which psoralen lesions induce these responses is not known.…”

Section: Resultsmentioning

confidence: 99%

“…However, psoralen-induced ICLs have been shown to induce DNA damage responses such as phosphorylation of the histone variant H2AX (␥H2AX) throughout the cell cycle and induce an arrest at the G 1 /S border of the cell cycle (Mogi et al, 2008;Viola et al, 2008). We and others have shown that agents that block transcription induce p53 (Yamaizumi and Sugano, 1994;Ljungman and Zhang, 1996;Ljungman and Lane, 2004) and apoptosis in human cells (Ljungman and Zhang, 1996;McKay et al, 1998;Brash et al, 2001).…”

mentioning

confidence: 99%

Psoralen-Induced DNA Interstrand Cross-Links Block Transcription and Induce p53 in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner

Derheimer¹,

Hicks²,

Paulsen³

et al. 2008

Mol Pharmacol

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Psoralen plus UVA light (PUVA) is commonly used to treat psoriasis, a common skin disorder associated with rapid proliferation of cells. PUVA exerts its antiproliferative activity through formation of DNA monoadducts and interstrand crosslinks (ICLs). However, this treatment may lead to skin malignancies as a direct result of inducing carcinogenic DNA damage. Inactivation of the p53 tumor suppressor gene is an important event in the development of skin cancer. p53 is rapidly phosphorylated and stabilized in response to DNA damage, and the induction of apoptosis by p53 is an important mechanism by which p53 exerts its tumor-suppressive activity. To better understand the mechanism by which PUVA treatment induces p53, we exposed human skin fibroblasts with PUVA under conditions that differentially produce monoadducts and ICLs and found that psoralen-induced ICLs induced phosphorylation of the Ser-15 site of p53 and apoptosis much more effectively than psoralen-induced monoadducts. The induction of p53 phosphorylation by psoralen ICLs did not require factors believed to be involved in the repair of psoralen ICLs [xeroderma pigmentosum (XP)-A, XP-C, XP-F, Cockayne's syndrome-B, Fanconi anemia] but did require the ataxia-telangiectasia and Rad3-related but not the ataxia-telangiectasia mutated kinase. Psoralen-induced ICLs blocked transcription and replication more efficiently than monoadducts, and induction of p53 and apoptosis correlated with doses causing interference with transcription rather than DNA replication. Our finding that cells underwent apoptosis preferentially during S-phase suggests that the combined blockade of transcription and DNA replication by psoralen ICLs during S-phase elicits a strong apoptotic response.

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DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Cited by 31 publications

References 47 publications

Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

Translesion Polymerase η Is Upregulated by Cancer Therapeutics and Confers Anticancer Drug Resistance

Psoralen-Induced DNA Interstrand Cross-Links Block Transcription and Induce p53 in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner

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