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      The Cellular Response to Transcription-Blocking DNA Damage

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          Abstract

          In response to transcription-blocking DNA lesions such as those generated by UV irradiation, cells activate a multipronged DNA damage response. This response encompasses repair of the lesions that stall RNA polymerase (RNAP) but also a poorly understood, genome-wide shutdown of transcription, even of genes that are not damaged. Over the past few years, a number of new results have shed light on this intriguing DNA damage response at the structural, biochemical, cell biological, and systems biology level. In this review we summarize the most important findings.

          Highlights

          Biochemical and genetic studies indicate crosstalk between TC-NER factors and factors regulating RNAPII backtracking and elongation.

          TC-NER is controlled by an unexpectedly complex layer of post-translational regulation targeting repair factors and RNAPII itself.

          Dramatic changes to the transcriptional program in response to UV irradiation have been revealed by high-throughput genome-wide and time-resolved measurements.

          Chromatin remodelers, splicing factors, noncoding RNAs, and RNA modifications provide a multifaceted transcriptional response to UV irradiation.

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          Most cited references78

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          The biology of chromatin remodeling complexes.

          The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.
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            ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks.

            DNA double-strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing yet untested hypothesis is that this function is conserved in the context of DSBs. Using a novel reporter that allows for visualization of repair protein recruitment and local transcription in single cells, we describe an ATM-dependent transcriptional silencing program in cis to DSBs. ATM prevents RNA polymerase II elongation-dependent chromatin decondensation at regions distal to DSBs. Silencing is partially dependent on E3 ubiquitin ligases RNF8 and RNF168, whereas reversal of silencing relies on the uH2A deubiquitylating enzyme USP16. These findings give insight into the role of posttranslational modifications in mediating crosstalk between diverse processes occurring on chromatin. Copyright 2010 Elsevier Inc. All rights reserved.
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              Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response.

              Execution of the DNA damage response (DDR) relies upon a dynamic array of protein modifications. Using quantitative proteomics, we have globally profiled ubiquitination, acetylation, and phosphorylation in response to UV and ionizing radiation. To improve acetylation site profiling, we developed the strategy FACET-IP. Our datasets of 33,500 ubiquitination and 16,740 acetylation sites provide valuable insight into DDR remodeling of the proteome. We find that K6- and K33-linked polyubiquitination undergo bulk increases in response to DNA damage, raising the possibility that these linkages are largely dedicated to DDR function. We also show that Cullin-RING ligases mediate 10% of DNA damage-induced ubiquitination events and that EXO1 is an SCF-Cyclin F substrate in the response to UV radiation. Our extensive datasets uncover additional regulated sites on known DDR players such as PCNA and identify previously unknown DDR targets such as CENPs, underscoring the broad impact of the DDR on cellular physiology.
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                Author and article information

                Contributors
                Journal
                Trends Biochem Sci
                Trends Biochem. Sci
                Trends in Biochemical Sciences
                Elsevier Trends Journals
                0968-0004
                1 May 2018
                May 2018
                : 43
                : 5
                : 327-341
                Affiliations
                [1 ]Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
                Author notes
                Article
                S0968-0004(18)30044-6
                10.1016/j.tibs.2018.02.010
                5929563
                29699641
                c9b54879-0952-4d08-a01b-6cf7e3f797f2
                © 2018 The Francis Crick Institute

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Categories
                Article

                Biochemistry
                dna damage response,nucleotide excision repair,transcription-coupled nucleotide excision repair,cockayne syndrome,uv-sensitivity syndrome,transcription restart

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