Higher-order chromatin structure in DSB induction, repair and misrepair

Falk, Martin; Lukášová, Emı́lie; Kozubek, Stanislav

doi:10.1016/j.mrrev.2010.01.013

Cited by 116 publications

(118 citation statements)

References 142 publications

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“…It has become increasingly clear that the chromatin compaction present in heterochromatin helps to protect DNA from damaging drugs. 17 As such, knockdown of heterochromatic proteins or induced de-condensation of chromatin sensitizes cells to DNA damages. 18 According to our data, HDAC5 depletion could expose heterochromatic regions to DNA-damaging drugs.…”

Section: Hdac5mentioning

confidence: 99%

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells

et al. 2012

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Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNAdamaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic.

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Section: Hdac5mentioning

confidence: 99%

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells

et al. 2012

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“…DNA repair is no exception, and dynamic changes in chromatin condensation and accompanying histone marks have been recognized as inevitable DDR pathways [15,[75][76][77][78][79][80]. Here, too, the DDR relies on recruitment of existing players in the chromatin organization arena [32][33][34][75][76][77][78][79][81][82][83][84][85].…”

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

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“…DSBs or SSBs induced in the DNA by endogenous processes or exogenous agents can in principle be repaired either by nonhomologous end joining (NHEJ) or homology directed repair (HDR). Studies have also shown that elevated rate of DNA nicks and double strand breaks in sperms of infertile men could lead to infertility and 50% of miscarriages; this means that these individuals have a background genetic instability that can be caused by their inability to repair DNA damage and are susceptible to mutagenic and clastogenic agents [27][28][29].…”

Section: Resultsmentioning

confidence: 99%

Increased frequency of micronuclei in lymphocytes of infertile males after exposure to gamma irradiation: a possible sign of genomic instability

Moghbelinejad

Mozdarani

Aleyasin

2011

J Assist Reprod Genet

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Purpose Induced chromosomal instability and micronucleus (MN) formation in blood lymphocytes of infertile men in comparison with fertile men exposed to gamma radiation was investigated. Methods Blood samples of healthy and infertile donors were irradiated by 2 and 4 Gy Co-60 gamma-rays, then cultured in RPMI-1640 complete medium containing 1% phytoheamaglutinin (PHA) and incubated in a CO 2 incubator. Cytochalasin-B was added to the cultures at a final concentration of 4 μg/ml. Finally, harvesting, slide making, and analysis were performed according to standard procedures. Results We observed a statistically significant difference between the frequencies of micronuclei in lymphocytes of infertile individuals, compared to healthy donors, before and after exposure to gamma rays. Although higher in azoospermia patients, the frequency of MN was not statistically different between infertile groups. Conclusions This study indicates that genomic instability in infertile men could probably contribute to the development of an impaired reproductive capacity.

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Higher-order chromatin structure in DSB induction, repair and misrepair

Cited by 116 publications

References 142 publications

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells

HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

Increased frequency of micronuclei in lymphocytes of infertile males after exposure to gamma irradiation: a possible sign of genomic instability

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