Poly(ADP-ribose) Polymerase 1 Is a Key Regulator of Estrogen Receptor α-dependent Gene Transcription

Zhang, Fengxiao; Yan, Wei; Wang, Lin; Luo, Xi; Huang, Kun; Wang, Cheng; Du, Meng; Liu, Fangmei; Luo, Ting; Huang, Dan; Huang, Kai

doi:10.1074/jbc.m112.429134

Cited by 57 publications

(46 citation statements)

References 33 publications

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“…The sexual dimorphism in our model may be explained by the interaction of Aag and Parp1 with estrogen receptor-α (ERα) [62, 63]. A direct interaction between Aag and ERα has been described; binding of Aag and ERα causes increased catalytic activity of Aag and decreased ERα-mediated transcription [62].…”

Section: Discussionmentioning

confidence: 99%

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

et al. 2016

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Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1−/−) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.

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Section: Discussionmentioning

confidence: 99%

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

et al. 2016

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“…In the case of PARP1, the enzyme ADP-ribosylates the ER to promote its binding to oestrogen response elements. As such, it is indispensable for ERα-mediated gene expression 67 .…”

Section: Repair Factors and Transcriptionmentioning

confidence: 99%

Physiological functions of programmed DNA breaks in signal-induced transcription

Puc

Aggarwal

Rosenfeld

2017

Nat Rev Mol Cell Biol

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The idea that signal-dependent transcription might involve the generation of transient DNA nicks or even breaks in the regulatory regions of genes, accompanied by activation of DNA damage repair pathways, would seem to be counterintuitive, as DNA damage is usually considered harmful to cellular integrity. However, recent studies have generated a substantial body of evidence that now argues that programmed DNA single- or double-strand breaks can, at least in specific cases, have a role in transcription regulation. Here, we discuss the emerging functions of DNA breaks in the relief of DNA torsional stress and in promoter and enhancer activation.

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“…PARylation of ER is required for ER binding to target sequences, as well as for ER target gene expression [59]. However, as with PR, the biological impact of PARP-1 regulation of ER is still unclear.…”

Section: Dna Repair Factors As Modulators Of Steroid Receptor Functionmentioning

confidence: 99%

Linking DNA Damage and Hormone Signaling Pathways in Cancer

Schiewer

Knudsen

2016

Trends in Endocrinology & Metabolism

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DNA damage response and repair (DDR) is a tightly controlled process that serves as a barrier to tumorigenesis. Consequently, DDR is frequently altered in human malignancy, and can be exploited for therapeutic gain either through molecularly targeted therapies, or as a consequence of therapeutic agents that induce genotoxic stress. In select tumor types, steroid hormones and cognate receptors serve as major drivers of tumor development/progression, and as such are frequently targets of therapeutic intervention. Recent evidence suggests the existence of crosstalk mechanisms linking the DDR machinery and hormone signaling pathways that cooperate to influence both cancer progression and therapeutic response. These underlying mechanisms and their implications for cancer management will be discussed.

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Poly(ADP-ribose) Polymerase 1 Is a Key Regulator of Estrogen Receptor α-dependent Gene Transcription

Cited by 57 publications

References 33 publications

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner

Physiological functions of programmed DNA breaks in signal-induced transcription

Linking DNA Damage and Hormone Signaling Pathways in Cancer

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