scholarly journals XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair

2021 ◽  
Author(s):  
Marek Adamowicz ◽  
Richard Hailstone ◽  
Annie A. Demin ◽  
Emilia Komulainen ◽  
Hana Hanzlikova ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Neurological Disease ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Toxic Activity ◽  
Single Strand Break ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

AbstractGenetic defects in the repair of DNA single-strand breaks (SSBs) can result in neurological disease triggered by toxic activity of the single-strand-break sensor protein PARP1. However, the mechanism(s) by which this toxic PARP1 activity triggers cellular dysfunction are unclear. Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1−/− mouse neurons. This defect is caused by excessive/aberrant PARP1 activity during DNA base excision repair, resulting from the loss of PARP1 regulation by XRCC1. We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation. Importantly, inhibition and/or deletion of PARP1 or USP3 restores transcriptional recovery in XRCC1−/− cells, highlighting PARP1 and USP3 as possible therapeutic targets in neurological disease.

scholarly journals Early Steps in the DNA Base Excision Repair Pathway of a Fission YeastSchizosaccharomyces pombe

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Kyoichiro Kanamitsu ◽  
Shogo Ikeda
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Alternative Pathway ◽  
Strand Break ◽  
Repair Pathway ◽  
Single Strand Break ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Lyase Activity ◽  
Base Excision

DNA base excision repair (BER) accounts for maintaining genomic integrity by removing damaged bases that are generated endogenously or induced by genotoxic agents. In this paper, we describe the roles of enzymes functioning in the early steps of BER in fission yeast. Although BER is an evolutionarily conserved process, some unique features of the yeast repair pathway were revealed by genetic and biochemical approaches. AP sites generated by monofunctional DNA glycosylases are incised mainly by AP lyase activity of Nth1p, a sole bifunctional glycosylase in yeast, to leave a blocked3′end. The major AP endonuclease Apn2p functions predominantly in removing the3′block. Finally, a DNA polymerase fills the gap, and a DNA ligase seals the nick (Nth1p-dependent or short patch BER). Apn1p backs up Apn2p. In long patch BER, Rad2p endonuclease removes flap DNA containing a lesion after DNA synthesis. A UV-specific endonuclease Uve1p engages in an alternative pathway by nicking DNA on the5′side of oxidative damage. Nucleotide excision repair and homologous recombination are involved in repair of BER intermediates including the AP site and single-strand break with the3′block. Other enzymes working in3′end processing are also discussed.

scholarly journals Distinct spatiotemporal patterns and PARP dependence of XRCC1 recruitment to single-strand break and base excision repair

2013 ◽  
Vol 41 (5) ◽  
pp. 3115-3129 ◽  
Author(s):  
Anna Campalans ◽  
Thierry Kortulewski ◽  
Rachel Amouroux ◽  
Hervé Menoni ◽  
Wim Vermeulen ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Spatiotemporal Patterns ◽  
Single Strand Break ◽  
Base Excision

scholarly journals Interaction with OGG1 Is Required for Efficient Recruitment of XRCC1 to Base Excision Repair and Maintenance of Genetic Stability after Exposure to Oxidative Stress

2015 ◽  
Vol 35 (9) ◽  
pp. 1648-1658 ◽  
Author(s):  
Anna Campalans ◽  
Eva Moritz ◽  
Thierry Kortulewski ◽  
Denis Biard ◽  
Bernd Epe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Main Function ◽  
Single Strand Break ◽  
Single Strand Break Repair ◽  
Base Excision ◽  
Epidemiology Studies

XRCC1 is an essential protein required for the maintenance of genomic stability through its implication in DNA repair. The main function of XRCC1 is associated with its role in the single-strand break (SSB) and base excision repair (BER) pathways that share several enzymatic steps. We show here that the polymorphic XRCC1 variant R194W presents a defect in its interaction with the DNA glycosylase OGG1 after oxidative stress. While proficient for single-strand break repair (SSBR), this variant does not colocalize with OGG1, reflecting a defect in its involvement in BER. Consistent with a role of XRCC1 in the coordination of the BER pathway, induction of oxidative base damage in XRCC1-deficient cells complemented with the R194W variant results in increased genetic instability as revealed by the accumulation of micronuclei. These data identify a specific molecular role for the XRCC1-OGG1 interaction in BER and provide a model for the effects of the R194W variant identified in molecular cancer epidemiology studies.

scholarly journals Lamin A/C promotes DNA base excision repair

2019 ◽  
Author(s):  
Scott Maynard ◽  
Guido Keijzers ◽  
Mansour Akbari ◽  
Michael Ben Ezra ◽  
Arnaldur Hall ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Nuclear Lamina ◽  
Strand Break ◽  
Premature Aging ◽  
Lamin A ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

Abstract The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

CK2 phosphorylation of XRCC1 facilitates dissociation from DNA and single-strand break formation during base excision repair

DNA Repair ◽  
2011 ◽  
Vol 10 (9) ◽  
pp. 961-969 ◽  
Author(s):  
Cecilia E. Ström ◽  
Oliver Mortusewicz ◽  
David Finch ◽  
Jason L. Parsons ◽  
Anne Lagerqvist ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Strand Break ◽  
Single Strand ◽  
Single Strand Break ◽  
Base Excision ◽  
Break Formation
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