The hardwired transcriptional response to DNA damage

Heilbrun, Elisheva E.; Merav, May; Parnas, Avital; Adar, Sheera

doi:10.1016/j.coisb.2020.05.001

Cited by 3 publications

(4 citation statements)

References 56 publications

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“…Although this pattern is not changed upon stress, we highlight a uniform gain at 5′ proximal regions on essentially all active genes, which is accompanied by a loss from distal gene body regions in all cell types tested. This UV-induced co-transcriptional H2Bub reshuffling reflects the widespread PPP release of transcription elongation waves that was reported previously [7] , [8] , [9] , [10] , [11] , [12] , [13] and may justify the rapid loss of H2Bub detected in extracts from UV-irradiated cells. Interestingly, we found that the extent of gain in H2Bub was uniform across all active genes and that the length of the 5′ regions associated with gain in H2Bub was equal, independently of gene or intron 1 length, indicating that changes in local RNAPII density and speed have a strong effect on H2Bub levels in chromatin.…”

Section: Introductionsupporting

confidence: 69%

“…In recent years, a number of labs have shed light on a multi-layered transcription-driven DDR mechanism that is activated in response to UV-C-induced genotoxic stress in human cells [7] , [8] , [9] , [10] , [11] , [12] , [13] ). This mechanism involves a prompt and synchronous release of promoter-proximal paused (PPP) RNA polymerase II (RNAPII) elongation complexes at early steps following damage induction.…”

Section: Introductionmentioning

confidence: 99%

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Histone H2Bub dynamics in the 5′ region of active genes are tightly linked to the UV-induced transcriptional response

Fanourgakis

Synacheri

Lavigne

et al. 2023

Computational and Structural Biotechnology Journal

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Section: Introductionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Histone H2Bub dynamics in the 5′ region of active genes are tightly linked to the UV-induced transcriptional response

Fanourgakis

Synacheri

Lavigne

et al. 2023

Computational and Structural Biotechnology Journal

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“…DNA repair is a process that requires time to be accurately accomplished, at the expense of transcription and replication dynamics 52,53 . We therefore asked whether the increased frequency of TRCs and sustained DDR activation observed in ANP32E-overexpressing cells might have some drawbacks on transcription and replication speeds.…”

Section: Resultsmentioning

confidence: 99%

ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer

Lago,

Poli,

Fol

et al. 2024

Preprint

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Oncogene-induced replicative stress (RS) plays a central role in tumor progression, leading to genomic instability by eliciting transcription replication conflicts (TRCs), which represent the major source of R-loops, that ultimately favors the onset of the DNA damage response (DDR). We investigated the pathogenic contribution of chromatin factors in increasing TRCs and R-loop frequencies in cancer. We found that in breast cancer patients the concomitant upregulation of MYC and the H2A.Z-specific chaperone ANP32E correlated with an increase the genome instability. Genome-wide profiling revealed that the ANP32E-dependent increases the turnover of H2A.Z altered RNApol II processivity, leading to the accumulation of long R-loops at TRCs. We showed that ANP32E upregulation increases TRCs and activates an ATR-dependent DDR, which predisposes cancer cells to R-loop-mediated genomic fragility. By exploiting the vulnerability of ANP32E-expressing cancer cells to ATR inhibitors, we found that tumors relied on this DDR pathway, whose inhibition halted their pro-metastatic capacity.

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“…The higher the frequency of TT, the higher the frequency of damage. The immediate consequence of these damages is inhibition of gene expression ( 26 , 27 ). The CPDs block elongating RNA Pol II and induce its subsequent degradation, resulting in a transcriptional shutdown.…”

Section: Introductionmentioning

confidence: 99%

Exons and introns exhibit transcriptional strand asymmetry of dinucleotide distribution, damage formation and DNA repair

Heilbrun

Merav

Adar

2021

NAR Genomics and Bioinformatics

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Recent cancer sequencing efforts have uncovered asymmetry in DNA damage induced mutagenesis between the transcribed and non-transcribed strands of genes. Here, we investigate the major type of damage induced by ultraviolet (UV) radiation, the cyclobutane pyrimidine dimers (CPDs), which are formed primarily in TT dinucleotides. We reveal that a transcriptional asymmetry already exists at the level of TT dinucleotide frequency and therefore also in CPD damage formation. This asymmetry is conserved in vertebrates and invertebrates and is completely reversed between introns and exons. We show the asymmetry in introns is linked to the transcription process itself, and is also found in enhancer elements. In contrast, the asymmetry in exons is not correlated to transcription, and is associated with codon usage preferences. Reanalysis of nucleotide excision repair, normalizing repair to the underlying TT frequencies, we show repair of CPDs is more efficient in exons compared to introns, contributing to the maintenance and integrity of coding regions. Our results highlight the importance of considering the primary sequence of the DNA in determining DNA damage sensitivity and mutagenic potential.

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The hardwired transcriptional response to DNA damage

Cited by 3 publications

References 56 publications

Histone H2Bub dynamics in the 5′ region of active genes are tightly linked to the UV-induced transcriptional response

Histone H2Bub dynamics in the 5′ region of active genes are tightly linked to the UV-induced transcriptional response

ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer

Exons and introns exhibit transcriptional strand asymmetry of dinucleotide distribution, damage formation and DNA repair

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