Unencumbered Pol β lyase activity in nucleosome core particles

Rodriguez, Yesenia; Howard, Michael J.; Cuneo, M.J.; Prasad, Rajendra; Wilson, Samuel H.

doi:10.1093/nar/gkx593

Cited by 20 publications

(19 citation statements)

References 64 publications

(109 reference statements)

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“…Such de-compaction may increase the access of Polβ to the damage site and enhance the enzymatic activity towards our NCP models. Moreover, an increase in Polβ activity after damage dislocation towards the blunt ends has been documented (72). Nevertheless, the proximity of the single-strand break to the blunt ends of DNA duplexes may start protein–protein competition for the substrate between PARP1 and Polβ.…”

Section: Discussionmentioning

confidence: 99%

The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context

Kutuzov

Belousova

Kurgina

et al. 2020

Preprint

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The repair processes regulation including base excision repair (BER) is implemented by a cellular signal PARylation catalysed by PARP1 and PARP2. Despite intensive studies, it is far from clear how BER is regulated by PARPs and how the roles are distributed between the PARPs. Here, we investigated the effects of PARP1, PARP2 and PARylation on activities of the main BER enzymes (APE1, Polβ and LigIIIα) in combination with XRCC1 in the nucleosomal context. We constructed nucleosomes with midward- or outward-oriented damage. It was concluded that in most cases, the presence of PARP1 leads to the suppression of the activities of APE1, Polβ, and to a lesser extent LigIIIα. PARylation by PARP1 attenuated this effect to various degrees. PARP2 had an influence predominantly on the last stage of BER: DNA sealing. Nonetheless, PARylation by PARP2 led to Polβ inhibition and to significant stimulation of LigIIIα activities in a NAD+-dependent manner.

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Section: Discussionmentioning

confidence: 99%

The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context

Kutuzov

Belousova

Kurgina

et al. 2020

Preprint

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“…Removal and repair of aberrant bases are dramatically impaired in the context of chromatinized DNA [9][10][11][12]36 . It has been suggested that for efficient repair within chromatin to take place, BER needs to be associated with essential nuclear processes, such as transcription 6 .…”

Section: Discussionmentioning

confidence: 99%

“…Association of AAG with transcription elongation could thus, in addition to enabling efficient removal of aberrantly methylated bases, serve as an important novel layer of gene expression control. 12…”

Section: Discussionmentioning

confidence: 99%

“…AAG activity is dramatically inhibited (84% to 100%) when the aberrant base is positioned mid-way or directly faces the surface of the histone octamer. Furthermore, the presence of nucleosomes was shown to significantly impair the activity of the downstream BER proteins APE1, DNA pol β and DNA ligase III/XRCC1 [10][11][12] . It was proposed that BER could overcome the inhibitory effect of nucleosomes by associating with processes that involve chromatin reorganization, such as replication and transcription [13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

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“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

Montaldo¹,

Bordin²,

Brambilla³

et al. 2019

Preprint

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Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG; aka MPG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here we show that AAG binds to chromatin and forms complex with active RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation.Importantly, at co-regulated genes aberrantly methylated bases accumulate towards 3'end, in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide novel insights to maintaining genome stability in actively transcribing chromatin, and reveal roles of aberrantly methylated bases in regulation of gene expression.

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“…Depending on the location of the substrate in the nucleosome, DNA glycosylases and APE1 have comparable activity on nucleosome substrates as with DNA, whereas some sites are completely inhibitory (31–34). The gap-filling activity of Pol β with nucleosome substrates is inhibitory (18,31,35–38). A question remains if BER enzymes can scan nucleosomal DNA to locate substrates and/or scan pass them.…”

Section: Processive Searching In Vivomentioning

confidence: 99%

DNA scanning by base excision repair enzymes and implications for pathway coordination

Howard

Wilson

2018

DNA Repair

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Site-specific DNA binding proteins must search the genome to locate their target sites, and many DNA modifying enzymes have the ability to scan along DNA in search of their substrates. This process is termed processive searching, and it serves to decrease the search time by effectively increasing the DNA binding footprint of a protein. The repertoire of proteins capable of processive searching is expanding, highlighting the need to understand the governing principles behind this fundamental process. Many of the enzymes in the base excision DNA repair pathway are capable of processive searching. Here, we briefly summarize methodology for determining if a protein can scan DNA and highlight the discovery that the base excision repair DNA polymerase β performs a processive search. Elucidation of physical models for DNA searching has also provided a plausible mechanism for pathway coordination during repair. The ability of BER enzymes to transiently sample adjacent DNA sites while bound to their product confers accessibility to downstream enzymes and does not require protein-protein interactions for coordination.

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Unencumbered Pol β lyase activity in nucleosome core particles

Cited by 20 publications

References 64 publications

The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context

The contribution of PARP1, PARP2 and poly(ADP-ribosyl)ation to base excision repair in the nucleosomal context

“Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression”

DNA scanning by base excision repair enzymes and implications for pathway coordination

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