Global Repair Profile of Human Alkyladenine DNA Glycosylase on Nucleosomes Reveals DNA Packaging Effects

Kennedy, Erin E.; Li, Chuxuan; Delaney, Sarah

doi:10.1021/acschembio.9b00263

Cited by 23 publications

(42 citation statements)

References 32 publications

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“…Fast repair was observed in the nucleosome-depleted region around the TF binding site and linker DNA between two adjacent nucleosomes ( Figure 2 ). In contrast, slow repair was found near nucleosome peaks, which is consistent with previous studies showing inhibition of BER at the nucleosome dyad center ( Kennedy et al, 2019 ; Mao et al, 2017 ). These data indicate that BER is affected by the combined effects of TF binding and nucleosome positioning.…”

Section: Resultssupporting

confidence: 92%

High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

Duan

Sivapragasam

Antony

et al. 2022

eLife

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DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), and characterized alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data shows that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs Abf1 and Reb1, but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. Repair of UV damage by nucleotide excision repair (NER) was also inhibited by TF binding. Interestingly, TF binding inhibits a larger DNA region for NER relative to BER. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.

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Section: Resultssupporting

confidence: 92%

High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

Duan

Sivapragasam

Antony

et al. 2022

eLife

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“…2A and 2B). In contrast, slow repair was found near nucleosome peaks, which is 171 consistent with previous studies showing inhibition of BER at the nucleosome dyad 172 center (Kennedy et al, 2019;Mao et al, 2017). A closer examination of remaining 173 damage indicates that repair was suppressed in an ~30-40 bp DNA region including the 174 conserved core motif and its immediately adjacent DNA (Fig.…”

Section: Abf1 and Reb1 Binding Inhibits Repair Of 7meg Lesions 155supporting

confidence: 88%

High-resolution mapping of DNA alkylation damage and base excision repair at yeast transcription factor binding sites

Duan

Sivapragasam

Antony

et al. 2021

Preprint

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DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, N-methylpurine-sequencing (NMP-seq), to characterize alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data shows that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs Abf1 and Reb1, but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.

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“…If UV-DDB aids in the removal of alkylation damage in chromatin, then it is possible this latter result is due to a decrease in the removal of potentially mutagenic methylated bases. Many DNA glycosylases appear to be inhibited in their ability to remove damaged bases in the context of nucleosomes [86][87][88][89][90]. Since UV-DDB has been found to bind to abasic sites embedded in nucleosomes in any orientation [60] and also alter the register of DNA lesions on nucleosomes [61], it is possible that UV-DDB binding directly to damage sites or through its associated E3 ligase activity may work to facilitate the removal of damaged bases during BER.…”

Section: Discussionmentioning

confidence: 99%

Expanding molecular roles of UV-DDB: Shining light on genome stability and cancer

et al. 2020

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UV-damaged DNA binding protein (UV-DDB) is a heterodimeric complex, composed of DDB1 and DDB2, and is involved in global genome nucleotide excision repair. Mutations in DDB2 are associated with xeroderma pigmentosum complementation group E. UV-DDB forms a ubiquitin E3 ligase complex with cullin-4A and RBX that helps to relax chromatin around UV-induced photoproducts through the ubiquitination of histone H2A. After providing a brief historical perspective on UV-DDB, we review our current knowledge of the structure and function of this intriguing repair protein. Finally, this article discusses emerging data suggesting that UV-DDB may have other non-canonical roles in base excision repair and the etiology of cancer. Introduction.Life has evolved a series of pathways to remove specific types of DNA damage. Nucleotide excision repair (NER) is dedicated to the removal of a wide variety of helix distorting lesions, including: ultraviolet (UV) photolesions, cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PP); bulky adducts formed by chemical carcinogens, such as polycyclic aromatic hydrocarbons; and certain DNA lesions formed from chemotherapeutic agents, like cisplatin. NER consists of two sub-pathways: global genome NER (GG-NER) #

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Global Repair Profile of Human Alkyladenine DNA Glycosylase on Nucleosomes Reveals DNA Packaging Effects

Cited by 23 publications

References 32 publications

High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

High-resolution mapping demonstrates inhibition of DNA excision repair by transcription factors

High-resolution mapping of DNA alkylation damage and base excision repair at yeast transcription factor binding sites

Expanding molecular roles of UV-DDB: Shining light on genome stability and cancer

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