当前位置： SCI文献检索 > MOLECULAR PHARMACOLOGY期刊下所有文献 > Psoralen-induced DNA interstrand cross-links block transcription and induce p53 in an ataxia-telangiectasia and rad3-related-dependent manner.

Psoralen-induced DNA interstrand cross-links block transcription and induce p53 in an ataxia-telangiectasia and rad3-related-dependent manner.

Abstract：

: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 cross-links (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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Derheimer FA,Hicks JK,Paulsen MT,Canman CE,Ljungman M

doi

10.1124/mol.108.051698

subject

Has Abstract

pub_date

2009-03-01 00:00:00

pages

599-607

issue

3

eissn

0026-895X

issn

1521-0111

pii

mol.108.051698

journal_volume

75

pub_type

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