How Is Dna Repaired During Transcriptions

Mol Cell. Author manuscript; available in PMC 2022 November seven.

Published in final edited form as:

PMCID: PMC3919531

NIHMSID: NIHMS534142

The Intertwined Roles of Transcription and Repair Proteins

Yick Westward. Fong

¹Howard Hughes Medical Found, Section of Molecular and Jail cell Biology, Academy of California, Berkeley, CA 94720, The states

Claudia Cattoglio

ⁱHoward Hughes Medical Institute, Section of Molecular and Prison cell Biology, University of California, Berkeley, CA 94720, Usa

Robert Tjian

¹Howard Hughes Medical Constitute, Department of Molecular and Cell Biology, Academy of California, Berkeley, CA 94720, Us

²Li Ka Shing Eye for Biomedical and Wellness Sciences, University of California, Berkeley, CA 94720, United states

Abstract

Transcription is patently risky business. Its intrinsic mutagenic potential must be kept in check by networks of Dna repair factors that monitor the transcription procedure to repair Deoxyribonucleic acid lesions that could otherwise compromise transcriptional fidelity and genome integrity. Intriguingly, recent studies point to an even more straight function of DNA repair complexes as co-activators of transcription and the unexpected part of "scheduled" Dna damage/repair at factor promoters. Paradoxically, spontaneous Dna double-strand breaks too induce ectopic transcription that is essential for repair. Thus, transcription, DNA damage and repair may be more than physically and functionally intertwined than previously appreciated.

Introduction

Accurate processing of genetic information by transcription is vital for development and survival of the organism. Execution of these factor expression programs in a stage- and jail cell type-specific manner requires the coordinated assembly of the transcription apparatus at select factor promoters (Lemon and Tjian, 2000). Transcriptional activation involves the initial recognition of key regulatory DNA elements at promoters by sequence-specific DNA-bounden activators and the core transcription machinery, forth with the recruitment of essential cofactors (Fong et al., 2022; Lemon and Tjian, 2000; Naar et al., 2001; Roeder, 2005). Within this large poly peptide ensemble termed the preinitiation circuitous (PIC), a serial of enzymatic reactions and extensive remodeling of protein-Deoxyribonucleic acid and protein-protein transactions must occur earlier transcription commences (He et al., 2022).

The highly choreographed cascade of events leading to factor activation provides numerous points of regulation and fine tuning. This remarkable flexibility, a necessary property to ensure target specificity and transcriptional fidelity, besides makes transcription particularly sensitive to perturbations in the genome including DNA damage. Chromosomal Deoxyribonucleic acid is under relentless attack from both endogenous byproducts of cellular metabolism (e.thou. reactive oxygen species) and exogenous sources of environmental stress (e.grand. ultraviolet calorie-free). These genotoxic agents create Dna breaks and adducts that, if left unresolved, tin can exist detrimental to both Dna replication and transcription, and, ultimately, cell function and survival (Hoeijmakers, 2001). These genomic insults may be especially pertinent to stem cells where the consequences of unrepaired Deoxyribonucleic acid impairment tin be profound. Mutations acquired by stem cells become amplified through self-renewal and, at the same fourth dimension, propagated to progenitor cells that tin differentiate to form a substantial part of a tissue, or in the case of embryonic stem cells, an entire organism (Mandal et al., 2022). In fact, proliferation of these damaged cells often manifests itself in diseases such as premature aging, developmental disorders and cancer (Diderich et al., 2022; Iyama and Wilson, 2022).

Because the frequency at which Deoxyribonucleic acid damage occurs (~x^four events per day (Lindahl and Barnes, 2000)) and the broad spectrum of damage incurred past a cell, information technology is remarkable that the overwhelming majority of these offending DNA lesions are repaired with impressive accuracy and efficiency. Indeed, cells accept evolved multiple, often overlapping, mechanisms to sense and demarcate the DNA lesions, while their repair is carried out by one (or more than) of the iv major pathways: base of operations excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR) and recombinational repair (Figure ane and run across reviews (Iyama and Wilson, 2022; Sancar et al., 2004)).

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Major DNA repair pathways in mammals

Exogenous and endogenous genotoxic agents (top) generate a multifariousness of Deoxyribonucleic acid damage, such every bit single and double strand breaks (SSBs, DSBs), insertions and deletions (indels). Lesions are detected and repaired by four major Deoxyribonucleic acid repair pathways: base excision repair (BER, A), nucleotide excision repair (NER, B), mismatch repair (MMR, C) and recombinational repair (D). Mechanisms of BER, NER and recombinational repair are depicted. For each pathway, factors discussed in this review are in colors.

A. Removal of uracil from DNA by BER. Thymine DNA glycosylase (TDG) removes the nitrogenous base and generates an abasic site (*). Apurinic/apyrimidinic (AP) endonuclease finalizes the nucleotide removal and creates a nick in the sugar-phosphate backbone. Poly ADP-ribose polymerase 1 (PARP-1) senses the SSB and recruits DNA polymerase and ligase to make full in the gap.

B. Removal of large bulky adducts by NER. Transcribing RNA polymerase Two (Politico II) stalls at Dna lesions and triggers transcription-coupled NER (TCR). TCR is initiated by the recruitment of Cockayne syndrome proteins A and B (CSA, CSB) to the arrested polymerase. DNA damage on the non-transcribed regions of the genome is repaired past global genome NER (GGR) instead. Dna lesion is recognized by the repair complex comprising Xeroderma pigmentosum C (XPC), RAD23B and Centrin 2 (CETN2). Completion of TCR and GGR requires the recruitment of downstream NER factors (XPA, RPA, TFIIH, ERCC1-XPF, XPG). ERCC1-XPF and XPG endonucleases incise the damaged strand a few bases five′ and 3′ to the DNA lesion, respectively. The gap is filled in by DNA polymerase and sealed past ligase.

D. Removal of DSBs and inter-strand cantankerous-links (ICL) by recombinational repair. i. Repair of DSBs by not-homologous end joining (NHEJ). DSB sites are marked by Ataxia telangiectasia mutated (ATM) kinase-mediated phosphorylation of histone H2A variant X (γ-H2AX) (Burma et al., 2001). Ku proteins directly the binding of the catalytic subunits of the DNA-dependent protein kinase (DNA-PKcs) to the exposed Deoxyribonucleic acid ends. Autophosphorylation of Deoxyribonucleic acid-PKcs facilitates Deoxyribonucleic acid-ends processing and resealing.

2. Repair of ICLs by Fanconi Anemia (FA), homologous recombination (HR) and NER pathways (come across review (Deans and West, 2022)). During S-phase, converging replication forks stall at ICLs and are sensed by FANCM protein, which recruits downstream FA proteins (FA core) and initiates ATR (ATM- and Rad3-related)-CHK1 checkpoint response. The FA core complex ubiquitinates FANCD2 and FANCI. This facilitates the recruitment of endonucleases (SLX4, XPF/ERCC1, MUS81/EME1) and resection of the lesion from 1 of the two cross-linked strands. Translesion DNA synthesis proceeds through the uncut strand, generating the template for the homologous recombination machinery (MRN, BRCA2, RAD51) to complete Deoxyribonucleic acid replication across the nicked DNA strand. NER removes the remaining adducts.

Given that transcription and Deoxyribonucleic acid repair both involve intimate transactions with DNA, it is peradventure not surprising that these 2 processes are often coupled and, as we shall hash out in this review, perchance also interdependent and cross functional. It is well known that there is preferential repair of the transcribed Deoxyribonucleic acid strand in expressed genes by transcription-coupled repair (TCR), a sub-pathway of NER (Hanawalt and Spivak, 2008; Mellon et al., 1987). Primal to this repair process is the recruitment of Cockayne Syndrome B (CSB), TFIIH, and Xeroderma pigmentosum G (XPG) to RNA polymerase II arrested at damaged site (Saxowsky and Doetsch, 2006; Svejstrup, 2002). In improver, all three factors take well-divers roles in transcription (Citterio et al., 2000; Ito et al., 2007; Schaeffer et al., 1993) while XPG and TFIIH are also key players in global genome repair (GGR), the other co-operative of NER, thus highlighting the interconnected nature of transcription and DNA repair (Kamileri et al., 2022a). In this review, we discuss contempo findings suggesting a more complex, unanticipated interplay between transcription and Deoxyribonucleic acid repair across TCR. A growing list of proteins and protein complexes that were long idea to function exclusively in DNA repair are revealing themselves to be involved in transcription also. In catastrophic events similar double strand breaks (DSBs), impairment-induced ectopic transcription at such lesion appears to be an essential initiating event of the repair process. On the other hand, there is likewise accumulating evidence pointing to a role of eliciting DNA damage at gene promoters that can influence transcriptional activation. This extensive two-mode crosstalk betwixt transcription and Deoxyribonucleic acid repair may arise in part from the fact that transcription is an inherently mutagenic process.

Dna repair factors that double every bit transcription factors

Mutations in NER factors CSB, XPG, and the helicase subunits of TFIIH (XPB and XPD) generate complex multi-symptom phenotypes that cannot be readily explained by defects in Dna repair alone. The realization that the same set of proteins as well participates in transcriptional control resolved this long standing puzzle by pointing to a transcriptional component in affliction etiology (Compe and Egly, 2022; Kamileri et al., 2022a). Since then, more factors in the NER and other repair pathways take also been implicated in transcriptional activation (Bradsher et al., 2002; Fong et al., 2022; Iben et al., 2002; Le May et al., 2010a). By taking total advantage of their DNA nuclease, glycosylase, or helicase and related ATPase activities, repair proteins facilitate the remodeling of the epigenetic landscape and topology of chromatin at gene promoters. Peradventure more surprisingly, they can also recruit cofactors and/or interface with the transcription apparatus by acting as classical transcriptional activators and co-activators (Table 1 and Figure 2).

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Proteins classically ascribed to Deoxyribonucleic acid repair as well participate in transcriptional control

A–B. Nucleotide excision repair (NER). A. XPC potentiates transcriptional activation of nuclear receptors (NR) by nucleating the assembly of the unabridged NER mechanism at the promoter (TATA) of responsive genes (RARβ2, retinoic acid receptor β2 gene). XPG and ERCC1-XPF endonucleases create DNA nicks, enabling DNA demethylation (open circles correspond demethylated cytosines; filled circles denote five-methylcytosines) at gene promoter and terminator (TER), CTCF recruitment and looping between proximal and distal regulatory elements (DE, distal enhancer). B. In embryonic stem cells, the XPC circuitous functions every bit a transcriptional co-activator for stem jail cell-specific transcription factors OCT4 and SOX2 to maintain pluripotency. The mechanism by which the XPC complex stimulates transcription remains to be elucidated (dashed arrow). XPC tin potentially regulate transcription past stimulating TDG-mediated Deoxyribonucleic acid demethylation at cistron regulatory regions. Cytosines tin exist converted back to v-methylcytosines past Deoxyribonucleic acid methyltransferases (DNMTs).

B. Base of operations excision repair (BER). Thymine DNA glycosylase (TDG) bridges CBP/p300 histone acetyltransferase to sequence specific transcription factors (RAR/RXR, c-JUN, ERα) and participates in active DNA demethylation at promoters (TATA) of transcriptionally-poised, developmentally-regulated genes. Re-methylation of DNA is carried out by DNMTs.

C. Inter-strand cross-link repair (ICL). Upon DNA damage, mono-ubiquitinated Fanconi anemia poly peptide D2 (FANCD2) and its repair partner SLX4/FANCP demark and activate cistron promoters that are implicated in tumor suppression and cellular senescence (e.g., TAp63, BRCA2). The mechanism by which FANC proteins activate transcription is unclear (dashed arrow).

Table i

DNA repair factors involved in repair and transcription

Poly peptide (Official Proper name)	Repair Pathway	Enzymatic Activity	Function in DNA Repair	Function in Transcription
CSB (ERCC6)	TCR (NER)	DNA-dependent ATPase	Initiates TC-NER at stalled Pol Two	Functions as an ATP-dependent chromatin remodeler Stimulates transcription past Pol I and Ii
DNA-PKcs	NHEJ BER	Protein kinase	Facilitates Dna end processing and resealing in NHEJ by autophosphorylation May stimulate BER of oxidative Dna damage	Facilitates cistron activation past chromatin remodeling Modulates the activity of transcription factors
FANCD2	ICL	[ND]	Initiates ICL repair	Activates transcription of TAp63 and promotes senescence of tumorigenic cells
FANCP (SLX4)	ICL	[ND]	Acts equally a scaffold for multiple structure- specific endonucleases	Cooperates with FANCD2 in transcriptional activation of TAp63
TFIIH	TCR (NER) GGR (NER)	ATP-dependent Dna helicase Protein kinase	Unwinds the Deoxyribonucleic acid at damaged sites Facilitates XPF incision	Unwinds the DNA at gene promoters Phosphorylates Pol 2 carboxy-last domain Phosphorylates NRs and co-activators
PARP-1	NHEJ HR BER NER	Deoxyribonucleic acid-dependent poly(ADP- ribosyl)transferase	Interacts physically and functionally with components in NHEJ, HR, BER and NER pathways	Modulates chromatin structure Functions every bit activator/co-activator or repressor Poly(ADP-ribosyl)ates chromatin remodeling factors
TDG	BER	DNA glycosylase	Excises damaged nitrogenous bases	Regulates Deoxyribonucleic acid demethylation at gene regulatory regions Bridges CBP/p300 to transcription factors and NRs
XPC-RAD23B-CETN2	GGR (NER) BER	[ND]	Initiates GGR at bulky Deoxyribonucleic acid lesions Stimulates TDG-mediated BER	Activates transcription at NR target genes Functions as a co-activator for OCT4 and SOX2 in embryonic stalk cells
XPF (ERCC4)	TC-NER GG-NER ICL	Structure-specific endonuclease	Incises the damaged strand 5′ to the Dna lesion	Promotes active Dna demethylation at terminators of NR targets Recruits CTCF and facilitates Dna looping at NR targets Stimulates transcription initiation
XPG (ERCC5)	TCR (NER) GGR (NER)	Structure-specific endonuclease	Incises the damaged strand iii′ to the Dna lesion	Stabilizes TFIIH Promotes active Deoxyribonucleic acid demethylation at promoters of NR targets Recruits CTCF and facilitates DNA looping at NR targets

Nucleotide excision repair

XPC is a member of the Xeroderma pigmentosum family that is dispensable for TCR but essential for initiating GGR (Venema et al., 1990). If XPC functions purely every bit a sensor for bulky DNA lesions, scanning for harm past XPC ought to be transient (Camenisch et al., 2009), and its interaction with DNA should display neither sequence nor positional preference. Instead, in HeLa cells and human fibroblasts, XPC was found to bind hormone-inducible gene promoters (e.g. RARβ2) and nucleate the assembly of an entire NER complex in a transcription-dependent but Deoxyribonucleic acid damage-contained manner, thus arguing for an expanded part of NER factors in gene regulation (Le May et al., 2010b) (Figure 2A). Indeed, depletion of XPC disrupted NER complex assembly at RARβ2 and significantly attenuated its transcriptional response to retinoic acid consecration. Optimal expression of RARβ2 requires Deoxyribonucleic acid breaks elicited by endonucleases XPG and XPF, which, past a nonetheless unknown mechanism, enable CTCF recruitment and gene looping (Le May et al., 2022). These coordinated events are accompanied by active DNA demethylation that could depend on the DNA impairment-inducible poly peptide GADD45A, although its interest remains controversial (Barreto et al., 2007; Jin et al., 2008; Schmitz et al., 2009). Consistent with these observations, the ERCC1-XPF circuitous has as well been shown to regulate transcription initiation of genes associated with growth in mice (Kamileri et al., 2022b).

Information technology is worth noting that the absenteeism of NER factors blunted but did non abolish transcriptional activation of only a subset of genes (Le May et al., 2010b). The intrinsic affinity of XPC for Dna (Krasikova et al., 2022) alone cannot explicate how XPC is directed to this subset of hormone-inducible and transcriptionally-poised gene promoters. Instead, we favor a model where XPC is recruited to promoters by cistron-specific activators, or potentially through recognition of DNA bends and distortions induced by bounden of nuclear hormone receptors to their cognate response elements (Nardulli and Shapiro, 1993; Robinson et al., 1998; Sugasawa et al., 2001). Assembly of the NER complex at factor promoters can be further stabilized past interactions with core components of the Motion picture (Kamileri et al., 2022b; Yokoi et al., 2000). Therefore, Deoxyribonucleic acid repair factors may deed as "facilitators" of gene activation by creating a favorable structural and epigenetic configuration for transcription in a gene- and possibly jail cell blazon-specific style.

Additional prove of cell type-specific transcriptional regulation by NER factors came from a recent study using an unbiased in vitro reconstituted system to biochemically screen for factors that are required for transcription of the stem cell pluripotency factor Nanog (Chambers et al., 2003; Mitsui et al., 2003). The employ of a highly integrated in vitro transcription analysis uncovered an activity enriched in an embryonic stalk (ES) cell nuclear extract that is essential for the key stem jail cell-specific activators OCT4 and SOX2 to activate Nanog (Fong et al., 2022). This newly detected activity turned out surprisingly to be the XPC-RAD23B-Centrin 2 complex (referred to every bit XPC time to come) (Araki et al., 2001) (Figure 2B). Although this result mirrors to some extent what is known about the function of XPC and other NER factors in general transcription, how XPC mediates OCT4/SOX2-specific activated transcription in ES cells seemed to differ fundamentally from its action in differentiated prison cell types in several respects. Showtime, XPC can straight potentiate the transcription of Nanog in the absence of other XP proteins (except TFIIH that is required to form an active prototypic PIC), suggesting that the assembly of a NER complex initiated by XPC and the subsequent Deoxyribonucleic acid breaks induced by XPF and XPG are disposable for Nanog activation at least in vitro. Furthermore, XPC occupies distal enhancers of a remarkably high number of OCT4/SOX2-target genes in ES cells (~70%) (Fong et al., 2022). Information technology as well became clear that XPC is not just a passive partner of OCT4 and SOX2 because disruption of the XPC complex compromises ES prison cell transcriptional responses, self-renewal and somatic cell reprogramming. Instead, a wealth of evidence suggests that XPC acts as a functionally important stem jail cell selective co-activator for OCT4 and SOX2 wherein XPC is recruited to enhancers likely via a straight interaction with the activators (Fong et al., 2022). Coopting a DNA repair factor by activators to drive stem cell-specific transcription may also provide the added benefits of protecting the integrity of genes essential for cocky-renewal and pluripotency from DNA damage (Etchegaray and Mostoslavsky, 2022).

Base excision repair

Active Deoxyribonucleic acid demethylation is thought to play a key role in transcriptional command and resetting of epigenetic retentivity during embryonic development and cellular reprogramming (Wu and Zhang, 2010). Although there are multiple mechanisms by which 5-methylcytosine (5mC) is removed in mammals, a mutual cease point to some of these processes appears to be excision of the deaminated and/or oxidized derivatives of 5mC by the BER enzyme thymine Deoxyribonucleic acid glycosylase (TDG) (Cortazar et al., 2007; Franchini et al., 2022). However, how prevalent and where TDG-mediated active Deoxyribonucleic acid demethylation occurs in the mammalian genome is not well understood. Four recent reports suggest that it is extensive (Cortazar et al., 2022; Cortellino et al., 2022; Shen et al., 2022; Vocal et al., 2022). Dynamic Dna demethylation occurs preferentially at promoters of silent and developmentally poised genes, and distal enhancers of active genes in mouse ES cells (Shen et al., 2022; Song et al., 2022). Given the pervasive nature of DNA methylation/demethylation in the genome, it was surprising that TDG knockdown in mouse ES cells simply afflicted the expression of a handful of genes. Apparently, agile Deoxyribonucleic acid demethylation at distal enhancers is dispensable for ongoing transcription. Presumably, the binding of regulatory factors (i.eastward. activators) is not particularly perturbed past the loss of regulated 5mC/C turnover at enhancers (Shen et al., 2022). On the other mitt, the ability to dynamically control DNA methylation homeostasis at promoters of developmentally- and transcriptionally-poised genes by TDG appears to be essential for the rapid and consummate transcriptional response to inducers like retinoic acid (Cortazar et al., 2022; Cortellino et al., 2022) (Effigy 2C). Therefore, TDG depletion evidently compromised primarily the reactivation of indicate-dependent and developmentally-poised genes during ES prison cell differentiation and embryogenesis. This may as well explain why TDG inactivation is embryonically lethal, a rather unusual phenotype given that many related DNA glycosylases are dispensable for embryogenesis (Cortazar et al., 2007).

Contained of its catalytic activity, TDG tin can also potentiate transcription by acting as a scaffold to bridge the transcriptional co-activator CBP/p300 to transcription factors like c-JUN (Chevray and Nathans, 1992), RAR/RXR (Cortellino et al., 2022; Um et al., 1998) and estrogen receptor α (ERα) (Chen et al., 2003) to facilitate histone modification (Figure 2C). Interestingly, the NER factor XPC has been shown to stimulate the DNA glycosylase activity of TDG via a directly interaction in vitro (Shimizu et al., 2010). This raises the intriguing possibility that XPC could likewise regulate transcription by coordinating with TDG and BER in active DNA demethylation at gene regulatory regions (Effigy 2B). Recently, it has been shown that the nigh dynamically regulated and differentially methylated regions (DMRs) across dissimilar cell types are overrepresented by enhancers and transcription gene bounden sites that display tissue or cell blazon-specific regulation (Ziller et al., 2022). In calorie-free of this finding, it is tempting to speculate that NER and BER factors could contribute to this procedure by cooperating with cell type-specific transcription factors.

Recombinational repair

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome characterized past developmental abnormalities, bone marrow failure and increased predisposition to squamous cell carcinoma of the skin (D'Andrea and Grompe, 1997). In response to Deoxyribonucleic acid damage that creates inter-strand cross-links, mono-ubiquitination of Fanconi anemia (FA) protein FANCD2 by the FA core complex facilitates the binding of FANCD2 to chromatin (Montes de Oca et al., 2005) and initiates the repair process by recruiting SLX4/FANCP and other downstream FA proteins (Yamamoto et al., 2022). Yet, a recent study uncovered an unanticipated role for the mono-ubiquitinated form of FANCD2 (FANCD2-Ub) in the transcriptional activation of the tumor suppressor gene TAp63 (Park et al., 2022). It is unclear how FANCD2-Ub regulates transcription, but its recruitment to the regulatory region of the TAp63 promoter is dependent on SLX4, presumably through the recognition of the ubiquitin moiety on FANCD2 past the ubiquitin bounden domains in SLX4. Genome-wide assay of FANCD2-Ub bounden sites identified many DNA harm-dependent or -enhanced targets including BRCA2, a key player in homologous recombination repair (Roy et al., 2022). This suggests that FANCD2-Ub and SLX4 may cooperate to generate a coordinated response to Dna impairment by repairing the lesion and possibly simultaneously interim as transcription factors to establish a gene expression program that promotes cellular senescence of damaged and potentially tumorigenic cells (Figure 2D). In fact, using the same DNA impairment-induced posttranslational modification (i.east. mono-ubiquitination) on FANCD2 as a trigger for both transcriptional activation and Deoxyribonucleic acid repair provides a potentially elegant solution to synchronizing the 2 processes. Information technology is worth noting that XPC is both ubiquitinated and sumoylated in response to UV-induced DNA damage (Sugasawa et al., 2005; Wang et al., 2005). It would therefore be of interest to examine the functional consequences of posttranslational modifications on XPC in transcription and DNA repair and the putative crosstalk between the two processes.

Transcription facilitates DNA damage

Equally vital as transcription is, information technology is not entirely an innocuous procedure. Transcription inevitably exposes the DNA template to attacks by genotoxic agents and generates potentially harmful Deoxyribonucleic acid structures that are prone to mutagenesis and recombination (Figure 3A). Oddly enough, gene activation sometimes also requires transient and localized Deoxyribonucleic acid damage at promoters that must exist repaired (Effigy 3B). Therefore, involvement of Deoxyribonucleic acid repair factors in transcriptional control might originate as an adaptive measure out by cells to preserve genetic information that evolved to have on additional roles in transcriptional regulation, thus further blurring the line between transcription and Deoxyribonucleic acid repair factors, and, to a certain extent, the processes they mediate.

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Transcription and Dna repair intersect

A. Transcription is a mutagenic process. R loops form when nascent messenger RNAs (mRNAs) hybridize dorsum to their template. Negative (−) and positive (+) supercoiling accumulate behind and ahead of elongating RNA polymerase 2 (Politician Two), and stabilize R loops. The displaced single-stranded Deoxyribonucleic acid is highly susceptible to chemical modifications (Deoxyribonucleic acid dissentious agents and deamination past activation-induced cytidine deaminase (AID)), and to the formation of recombinogenic secondary structures that are prone to transcription-associated mutagenesis (TAM) and recombination (TAR). Topoisomerase I (TopoI), RNase H, helicases and splicing factors (ASF/SF2) can foreclose or disrupt the formation of mutagenic R loop structures.

B. "Scheduled" DNA damage promotes transcriptional activation. Upon ligand bounden, estrogen receptor (ER) activates histone H3 demethylase LSD1 at responsive genes An external file that holds a picture, illustration, etc. Object name is nihms534142ig1.jpg . The demethylation reaction releases reactive oxygen species that converts nearby guanines (Grand) into 8-oxo-guanines (^oxG) . ^oxM removal by base excision repair (BER) creates Deoxyribonucleic acid nicks An external file that holds a picture, illustration, etc. Object name is nihms534142ig3.jpg that facilitate archway of the endonuclease topoisomerase IIβ (TopoIIβ) . TopoIIβ-induced double strand breaks recruit PARP-1 and Deoxyribonucleic acid-PKcs repair enzymes, which induce a permissive chromatin architecture for transcription initiation An external file that holds a picture, illustration, etc. Object name is nihms534142ig5.jpg .

Transcription-associated mutagenesis and recombination

The very act of transcription requires the separation of the two strands of a DNA double helix past RNA polymerase II (RNAPII). As RNAPII transverses the Deoxyribonucleic acid, negatively supercoiled DNA accumulated behind the advancing polymerase can crusade strand opening and expose unmarried-stranded (ss) regions to chemical modifications and genotoxic agents (Rahmouni and Wells, 1992). For case, deamination of cytosine by spontaneous hydrolysis or by activation-induced cytidine deaminase (Help)/APOBEC: a family unit of deaminases that preferentially target ssDNA regions that, if left unresolved by BER, could lead to C-to-T substitutions (Conticello, 2008; Frederico et al., 1990). In addition to nucleotide substitutions, ssDNA regions are prone to recombination as well as expansion and wrinkle of tri-nucleotide repeats. These likely ascend as a issue of attempts by transcription and replication enzymes to negotiate local secondary structures (due east.k. hairpins and loops) formed at Deoxyribonucleic acid sequence repeats (come across review (Kim and Jinks-Robertson, 2022)). Information technology therefore comes as no surprise that high levels of transcription are often associated with increased spontaneous rates of mutagenesis and recombination events in phenomena known every bit transcriptional-associated mutation (TAM) and transcription-associated recombination (TAR) (Aguilera, 2002; Lippert et al., 2022; Mischo et al., 2022; Takahashi et al., 2022).

The good and bad of R loops

R loops are three-stranded nucleic acrid structures containing an RNA-DNA duplex and a displaced, single stranded DNA (Reaban et al., 1994). They occur naturally during lagging strand Dna synthesis when DNA primase synthesizes a short RNA oligomer on ssDNA, and during transcription in the course of a transient hybrid between the newly synthesized messenger RNA (mRNA) and the template DNA at the catalytic center of RNAPII, where the length of the RNA-Deoxyribonucleic acid hybrid tin dictate stability and processivity of the transcription circuitous (Bochkareva et al., 2022; Nudler, 2022). The recombinogenic potential of R loop is highlighted in immunoglobulin (Ig) class switch recombination (CSR) at the Ig heavy chain locus, a process that is critical to diversifying the antibiotic repertoire during an immune response (Lieber, 2010). Transcription through the K-rich switch (S) regions generates R loops that can exceed ane kilobase in size (Yu et al., 2003). This enables AID-dependent modification of the displaced ssDNA. Deamination of cytosine to uracil by AID is thought to provoke base excision by the BER factor uracil Dna glycosylase, followed by recruitment of endonucleases to create single- and double-strand breaks within the South region. Class switching as a result of forming new Southward-Southward junctions is and so achieved by the non-homologous finish joining (NHEJ) recombinational repair mechanism. R loops are therefore functionally of import regulatory structures that appear to impact a broad array of cellular processes (Aguilera and Garcia-Muse, 2022).

R loops are also sources of TAM and TAR (Figure 3A). In improver to an increased vulnerability of ssDNA regions to attacks by genotoxic agents and nucleases, the RNA-Dna hybrid in an R loop can potentially prime mistake-decumbent Deoxyribonucleic acid synthesis (Aguilera and Garcia-Muse, 2022). Every bit in the instance of CSR, ectopic R loops tin generate DNA strand breaks by nucleases and promote downstream recombination events (Li and Manley, 2006). Indeed, defects in the molecular pathways limiting R loop genesis and clearance have been linked to human diseases (Lin and Wilson, 2022; Yuce and West, 2022). Fortunately, redundant mechanisms exist to suppress ectopic R loop structures induced by transcription. DNA strand opening due to torsional strain generated by transcription (or replication) is counteracted past Topoisomerase I (TopoI) that removes Deoxyribonucleic acid supercoils. In fact, information technology has recently been shown that transcription of exceptionally long genes (>200 kilobases) is particularly sensitive to TopoI inactivation (King et al., 2022). A key step in R loop formation is the invasion and hybridization of the nascent mRNA to the template strand. It has been shown that blanket of mRNA past splicing gene ASF/SF2 precludes RNA-DNA hybridization by packaging nascent mRNA into ribonucleoprotein complexes (Li and Manley, 2005). RNA-Deoxyribonucleic acid hybrids can likewise exist removed through unwinding past helicases or digestion of the RNA moiety by RNase H (Aguilera and Garcia-Muse, 2022). Co-transcriptional R loops are therefore rare but highly confusing structures that pose major threats to genome stability when one of these fail-safe mechanisms is compromised (Gan et al., 2022; Wahba et al., 2022).

Transcriptional activation may require "scheduled" Deoxyribonucleic acid damage

Cells have developed multiple mechanisms to minimize the mutagenic potential of Deoxyribonucleic acid damage. In the case of DSBs in cistron bodies, Polycomb repressive complexes (PRCs) accumulate at break sites and are idea to mediate transcriptional silencing as an adaptive response to reduce interference between repair and the transcription appliance (Vissers et al., 2022). Transcriptional inhibition has also been observed in BER of oxidative DNA impairment sites that practise not arrest transcribing RNAPII (and therefore exercise not evoke TCR), likely as a preventive measure against miscoding past RNAPII (Khobta and Epe, 2022). While global impairment on Deoxyribonucleic acid is generally associated with gene silencing, targeted DSB formation and localized Dna base damage take been implicated in transcriptional activation past nuclear hormone receptors (Ju et al., 2006; Lin et al., 2009; Perillo et al., 2008). Eliciting a "scheduled" Deoxyribonucleic acid base of operations damage appears to exist a common first step in hormone-dependent activation. Liganded androgen receptor recruits AID to deaminate cytosine (Lin et al., 2009) while estrogen receptor activates resident lysine-specific demethylase 1 (LSD1) to demethylate histone iii lysine 9, an oxidative process that releases hydrogen peroxide and converts nearby guanines into eight-oxo-guanines (Perillo et al., 2008). Their ensuing repair by Deoxyribonucleic acid glycosylases is thought to generate transient DNA nicks that deed as entry points for DNA endonucleases similar Topoisomerase IIβ (TopoIIβ) (Ju et al., 2006; Perillo et al., 2008) or LINE-i repeat encoded ORF2 endonuclease (Lin et al., 2009). The resulting DSBs are thought to relax DNA strands and facilitate the recruitment of other damage sensing and DNA repair enzymes (e.1000. PARP-i and DNA-PK) to collectively induce a permissive chromatin architecture for transcriptional activation (Ju et al., 2006). These observations are reminiscent of the proposed role of DNA breaks induced by NER factors XPG and XPF in chromatin looping (Le May et al., 2022). Perchance relaxation of Dna strands via DSBs or nicks permits chromosome angle thereby facilitating enhancer-promoter communication and dynamic gene transcription (Figure 3B).

It is thus evident that DNA damage tin have contrary effects on transcription. We presume that there must exist a mechanism that enables cells to distinguish betwixt these "scheduled" DNA harm events linked to gene activation from those that ascend spontaneously and crusade undesirable consequences. Afterwards all, both processes could generate damage-induced associates of Deoxyribonucleic acid repair complexes that are, for all intents and purposes, highly similar if non identical to each other. Perhaps the transient nature of transcription-induced lesions like DSBs past TopoIIβ prevents them from eliciting a persistent DNA damage response (DDR) (Ciccia and Elledge, 2010). It is also likely that transcription can limit the amplification of a DDR past suppressing the accumulation and spreading of the phosphorylated form of histone variant H2AX (γ-H2AX) that would unremarkably mark DSB sites and promote the retention of repair factors (Iacovoni et al., 2010).

DNA harm induces "unscheduled" transcription

Efficient repair of DSBs by recombinational mechanisms (i.e. homologous recombination (Hr) or NHEJ) requires the coordinated action of factors that sense, mark and procedure the lesions before the repair mechanism tin can be recruited to the damage sites. Although there is a wealth of information on protein factors involved in the initial stage of DSB repair, ii recent studies point to an unanticipated function of small non-coding RNAs (ncRNAs) in repair that is conserved from plants to humans (Francia et al., 2022; Wei et al., 2022). These ~21 nucleotide curt ncRNAs, termed DSB-induced small RNAs (diRNAs), are derived from ectopic transcription induced at DSB sites and processed by machinery in the microRNA biogenesis pathway. They are proposed to guide downstream DSB repair proteins to damaged sites to facilitate the repair process (Francia et al., 2022). It would be of interest to examine whether diRNAs are also involved in the repair of physiological DSBs created in 5(D)J recombination and CSR during an immune response (Lieber, 2010).

It is worth noting that in Arabidopsis thaliana, plant-specific RNA polymerases Four and 5 are able to generate transcripts at and near DSB sites in both sense and antisense strands. In human cells, RNAPII can also initiate transcription from both strands but is clearly excluded from regions immediately surrounding the DSB sites (Wei et al., 2022). This is likely due to the mutual antagonism between γ-H2AX aggregating at DSB sites and RNAPII transcription (Iacovoni et al., 2010). This also underscores a primal difference in how RNAPIV/5 and RNAPII can or cannot navigate DSB sites. Since the experimentally-induced DSBs were created at a single divers position within the protein coding region of an integrated reporter (Wei et al., 2022), a more firsthand question is what drives ectopic initiation when regulatory sequences critical for the assembly of a typical Moving picture are likely absent-minded at DSB sites. Therefore, an alternative PIC recruitment mechanism must exist. Whether or not this DSB-induced Moving picture is identical to the "approved" Flick assembled at gene promoter remains to be elucidated. However, given the recent appreciation that the brand-up of a functional PIC is more than flexible than previously thought (D'Alessio et al., 2009; Goodrich and Tjian, 2010; Muller et al., 2010), and that many Dna repair factors can function as transcription factors, it is believable that in this context Deoxyribonucleic acid repair factors could directly recruit RNA polymerase to the damaged sites and initiate transcription. Thus, damage-induced PICs could be compositionally and perhaps functionally distinct from prototypical PICs.

Conclusion

In this review, nosotros accept examined diverse means in which Deoxyribonucleic acid repair factors can impact gene activation. Only they all share one common thread: DNA repair factors are often required for transcription of developmentally-regulated and activator-dependent genes, just less then for constitutive housekeeping transcription. Based on these observations, Dna repair factors likely facilitate de novo Motion picture assembly at gene promoters, a rate-limiting footstep for factor activation (Lemon and Tjian, 2000; Michel and Cramer, 2022), by facilitating chromatin remodeling and enhancer-promoter communication.

Development of a multicellular organism from a zygote is critically dependent on a highly controlled process of cellular proliferation and differentiation. Proper execution of these processes is largely regulated at the transcriptional level (Levine and Tjian, 2003). The reverse is besides true; reprogramming of cells with restricted developmental potential back to a pluripotent state requires dynamic changes in chromatin arrangement, histone/DNA modifications and reactivation of a complex transcriptome (Apostolou et al., 2022; Phillips-Cremins et al., 2022; Polo et al., 2022; Wei et al., 2022; Zhang et al., 2022). The expanded roles of DNA repair factors in transcriptional command may explain why inactivation of factors in the NER, Hour, NHEJ and Fanconi anemia (FA) repair pathways poses such stiff barriers to somatic cell reprogramming past OCT4, SOX2, KLF4 and c-MYC (Fong et al., 2022; Gonzalez et al., 2022; Molina-Estevez et al., 2022; Muller et al., 2022; Takahashi and Yamanaka, 2006). On the other paw, rapid ectopic induction of transcription of a large number of genes by these factors during the initial phase of reprogramming could promote TAM and TAR due to a surge in transcriptional load and replication stress (Helmrich et al., 2022), thus activating a DNA impairment response that is prohibitive to the conversion process (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marion et al., 2009; Utikal et al., 2009). This is consistent with the observation that there is a dramatic increment in frequency of DSBs, as marked by accumulation of γ-H2AX and FANCD2 foci, in partially reprogrammed cells (Gonzalez et al., 2022; Muller et al., 2022). Taken together, these finding suggest that a major threat to the intrinsic ability of somatic cells to reprogram could indeed come up from within.

Requirement of DNA repair factors in stem cell pluripotency and in development may non be just a preventive machinery to safeguard genome integrity merely besides a proactive machinery to ensure that their respective transcriptional programs are robust yet dynamic enough to alter in response to developmental cues. The "symbiotic" human relationship betwixt transcription and DNA repair may originate from the fact that integrity of one is dependent on the other.

Acknowledgments

The authors wish to give thanks M. Botchan, J-Yard. Egly, D. Rio and C. Inouye for disquisitional reading of the manuscript. C. Cattoglio is a postdoctoral fellow of California Institute for Regenerative Medicine (CIRM training plan TG2-01164).

Footnotes

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