The Fanconi anemia pathway in replication stress and DNA crosslink repair

Ma, Jones; Huang, Tony T.

doi:10.1007/s00018-012-1051-0

Cited by 24 publications

(22 citation statements)

References 119 publications

(172 reference statements)

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“…Mono-ubiquitination of FD2 (FD2-Ub) and FI (FI-Ub) is a key event in the activation of the FA pathway that contributes to the resolution of endogenous replication-coupled DNA inter-strand crosslinks (ICLs). In line with this, FD2-Ub and FI-Ub interact with and recruit DNA repair proteins at DNA damage foci for DNA repair (Jones and Huang, 2012). Moreover, FD2-Ub was shown to be necessary for coordinating the firing of replication origins in unperturbed conditions (Panneerselvam et al, 2014), while unmodified FD2 is involved in replisome surveillance (Lossaint et al, 2013).…”

Section: Introductionmentioning

confidence: 64%

RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

et al. 2016

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Oncogene-induced senescence (OIS) is a potent barrier for the transformation of pre-cancerous cells. The molecular pathways involved in the execution of OIS are still incompletely understood, but they include chronic DNA damage signaling and post-translational modifications of key factors. Here, we show that OIS-associated transcriptional downregulation of deubiquitinating enzyme USP1 triggers and maintains a DNA damage checkpoint response with atypical DNA lesions that is dependent on functional FANCD2-FI-ATR-CHK1-p53-CDKN1A signaling. We find that a reduced USP1 level causes aberrant aggregation of its target FANCD2 concomitant with replication stress, accumulation, and colocalization of γ-H2Ax and p53-binding protein 1 (53BP1) in large and unusual sparse DNA damage foci and an increased number of polyploid cells and cells arrested in G2/M, as well as a sensitization of senescence-bypassing cells to DNA interstrand crosslinking-mediated cell death. Our study identifies USP1 as a key senescence regulator controlling genomic integrity and a promising target for anti-cancer therapy.

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Section: Introductionmentioning

confidence: 64%

RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

et al. 2016

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“…26,27 Several reports have implicated the FA pathway proteins in maintaining genome integrity during DNA replication, transcription and replication stress. [28][29][30] Replication protein A (RPA) and Chk1 phosphorylation by ATR (Ataxia Telangiectasia and Rad3-related) kinase, or ssDNA detection serve as specific replication stress markers. 31 RPA protects single-stranded DNA at stalled replication forks 32 and immunofluorescence detection of RPA foci after 72 hours of TTFields exposure identified increased RPA recruitment in H1299 and H157 cells ( Supplementary Fig 01).…”

Section: Resultsmentioning

confidence: 99%

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

Karanam

Ding

Asaithamby

et al. 2020

Translational Research

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Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes. When markers of DNA replication stress as a result of TTFields exposure were examined, newly replicated DNA length was reduced with TTFields exposure time and there was increased R-loop formation. Furthermore, as cells were exposed to TTFields a conditional vulnerability environment developed which rendered cells more susceptible to DNA damaging agents or agents that interfere with DNA repair or replication fork maintenance. The effect of TTFields exposure with concomitant exposure to cisplatin or PARP inhibition, the combination of TTFields plus concomitant PARP inhibition followed by radiation, or radiation alone at the end of a TTFields exposure were all synergistic. Finally, gene expression analysis of 47 key mitosis regulator genes suggested that TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another, are likely initiated independently of one another. This suggests that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications. (Translational Research 2020; 217:33À46) Abbreviations: CI = combination index; DDR = DNA damage response; DSBs = double strand breaks; FA = Fanconi Anemia; GBM = glioblastoma; HSA = highest single agent; IR = ionizing radiation; NSCLC = nonÀsmall-cell lung cancer; RPA = replication protein A; TTFields = tumor treating fields

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“…According to the current model of replication-dependent ICL repair, a second adjacent fork converging onto the ICL may participate in the ICL repair process (Huang et al, 2013; Jones and Huang, 2012; Knipscheer et al, 2009; Kottemann and Smogorzewska, 2013; Zhang and Walter, 2014). This critical second fork may arise from the firing of additional adjacent origins.…”

Section: Discussionmentioning

confidence: 99%

ATR-Mediated Phosphorylation of FANCI Regulates Dormant Origin Firing in Response to Replication Stress

et al. 2015

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SUMMARY Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi Anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances and slowed proliferation rates. Intriguingly, ATR-mediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and links timely genome replication to DNA repair.

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The Fanconi anemia pathway in replication stress and DNA crosslink repair

Cited by 24 publications

References 119 publications

RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

RETRACTED: USP1 Regulates Cellular Senescence by Controlling Genomic Integrity

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

ATR-Mediated Phosphorylation of FANCI Regulates Dormant Origin Firing in Response to Replication Stress

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