A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors

Izhar, Lior; Adamson, Brittany Susan; Ciccia, Alberto; Lewis, Jedd; Pontano-Vaites, Laura; Leng, Yumei; Liang, Anna C.; Westbrook, Thomas F.; Harper, J. Wade; Elledge, Stephen J.

doi:10.1016/j.celrep.2015.04.053

Cited by 147 publications

(155 citation statements)

References 70 publications

(98 reference statements)

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“…Recent evidence has suggested that chromatin plays a major role in the UV-induced cellular response including regulation of gene expression changes (Andrade-Lima et al, 2015;Dawes et al, 2014;Dinant et al, 2013;Duan and Smerdon, 2014;Hassan et al, 2014;Izhar et al, 2015;Li et al, 2014;Sesto et al, 2002;Zhang et al, 2014). However, a detailed genomewide analysis to investigate the relationship of chromatin and gene expression changes was still missing.…”

Section: Discussionmentioning

confidence: 99%

“…An early and transient nucleosome destabilization at the site of damage has been shown (Rubbi and Milner, 2003;Lieberman, 1978, 1980;Smerdon et al, 1982), which allows binding of the repair machinery to DNA lesions before chromatin architecture is restored after the repair (the 'prime-repair-restore model') (Soria et al, 2012). In this direction, a recent study has shown that, upon UV irradiation, chromatin transiently undergoes de-condensation to allow binding of several repressive factors such as the polycomb complex component BMI1, the nucleosome-remodeling deacetylase complex (NuRD) as well as the heterochromatin protein HP1 and the HP1-binding protein 3 (HP1BP3) (Izhar et al, 2015). Another study proposes that during the response to UV irradiation, recruitment of repressive complexes induces condensation of chromatin to protect DNA from further potential damage (Burgess et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Dynamics of chromatin accessibility and epigenetic state in response to UV damage

Schick

Fournier

Thakurela

et al. 2015

Journal of Cell Science

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Epigenetic mechanisms determine the access of regulatory factors to DNA during events such as transcription and the DNA damage response. However, the global response of histone modifications and chromatin accessibility to UV exposure remains poorly understood. Here, we report that UV exposure results in a genome-wide reduction in chromatin accessibility, while the distribution of the active regulatory mark H3K27ac undergoes massive reorganization. Genomic loci subjected to epigenetic reprogramming upon UV exposure represent target sites for sequence-specific transcription factors. Most of these are distal regulatory regions, highlighting their importance in the cellular response to UV exposure. Furthermore, UV exposure results in an extensive reorganization of super-enhancers, accompanied by expression changes of associated genes, which may in part contribute to the stress response. Taken together, our study provides the first comprehensive resource for genome-wide chromatin changes upon UV irradiation in relation to gene expression and elucidates new aspects of this relationship.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

Schick

Fournier

Thakurela

et al. 2015

Journal of Cell Science

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“…More specifically, FUS participates in both homologous recombination (HR) and nonhomologous end joining (NHEJ)-directed DSB repair (6,7). The evidence suggesting a role for FUS in DNA repair is particularly intriguing for ALS pathogenesis, given growing evidence that RNA binding proteins are active in the prevention and repair of transcription-associated DNA damage (8)(9)(10)(11)(12). Other ALS-related RNAbinding proteins like SETX, EWSR1, and TAF15 have also been linked to DNA damage and repair, further suggesting the importance of a breakdown in this process in ALS pathogenesis (11,(13)(14)(15)(16).…”

Section: Dna Damage Response | Als | Transcription | R Loopmentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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“…Besides regulating chromatin accessibility [199], PARPs can act more specifically, as activators/co-activators or (co-) repressors for numerous TFs. PARP-1 modulation of transcription factors impacts both gene regulation and the recently identified role of TFs in DNA repair [84,124].…”

Section: Sirtuins and Parpsmentioning

confidence: 99%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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A b s t r a c tSirtuins vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-κB, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADPribose) polymerases (PARPs), a crucial and widespread class of NAD

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A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors

Cited by 147 publications

References 70 publications

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

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