ATM and SIRT6/SNF2H Mediate Transient H2AX Stabilization When DSBs Form by Blocking HUWE1 to Allow Efficient γH2AX Foci Formation

Atsumi, Yuko; Minakawa, Yusuke; Ono, M.; Dobashi, Sachiko; Shinohe, Keitaro; Shinohara, Atsushi; Takeda, Shunichi; Takagi, Motoki; Takamatsu, Nobuhiko; Nakagama, Hitoshi; Teraoka, Hirobumi; Yoshioka, Ken

doi:10.1016/j.celrep.2015.11.054

Cited by 84 publications

(93 citation statements)

References 43 publications

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“…Previous work has shown that, in response to treatment with the DNA damage agent neocarzinostatin (NCS), H2A.X is rapidly phosphorylated on Ser139, which results in the stabilization of H2A.X protein (Atsumi et al, 2015). This extra H2A.X is then degraded as cells repair the DNA damage and recover from the genotoxic stress.…”

Section: Resultsmentioning

confidence: 99%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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Summary SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent γH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress.

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Section: Resultsmentioning

confidence: 99%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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“…2). Another histone that can be ubiquitin-modified by HUWE1 is H2AX, which is maintained at a low level in resting cells [141] but stabilized and phosphorylated to produce γH2AX at DNA double-strand breaks (DSBs) [142]. Atsumi et al have shown that H2AX is poly-ubiquitinated by HUWE1 and subject to degradation.…”

Section: Substrates Of Huwe1mentioning

confidence: 99%

“…Atsumi et al have shown that H2AX is poly-ubiquitinated by HUWE1 and subject to degradation. Upon DSBs, H2AX is dissociated from HUWE1 and enhances incorporation with chromatin regulated by SIRT6 and SNF2H [142] (Fig. 4).…”

Section: Substrates Of Huwe1mentioning

confidence: 99%

Ubiquitination by HUWE1 in tumorigenesis and beyond

Kao

2018

J Biomed Sci

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Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

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“…γ H2AX is a variant of the H2A histone family that is phosphorylated on Ser139 by ATM and ATM-Rad3-related (ATR) in the PI3K pathway of DNA repair and functions to recruit other DNA repair proteins in response to DNA damage [57, 58]. Importantly, γ H2AX foci form in response to DSBs [57], and the presence of foci can be utilized as a biomarker to measure DNA damage induced by PARP inhibition [59].…”

Section: Biomarkers In the Ddr Pathwaysmentioning

confidence: 99%

“…Importantly, γ H2AX foci form in response to DSBs [57], and the presence of foci can be utilized as a biomarker to measure DNA damage induced by PARP inhibition [59]. BRCA1 -mutated acute myeloid leukemia cells that were exposed to Olaparib subsequently formed γ H2AX foci, suggesting that γ H2AX foci formation may be a useful biomarker for successful PARP inhibition [59].…”

Section: Biomarkers In the Ddr Pathwaysmentioning

confidence: 99%

Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

Murata

Zhang

Finch

et al. 2016

BioMed Research International

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Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers.

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ATM and SIRT6/SNF2H Mediate Transient H2AX Stabilization When DSBs Form by Blocking HUWE1 to Allow Efficient γH2AX Foci Formation

Cited by 84 publications

References 43 publications

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

Ubiquitination by HUWE1 in tumorigenesis and beyond

Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

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