scholarly journals PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

2018 ◽  
Author(s):  
George E. Ronson ◽  
Ann Liza Piberger ◽  
Martin R. Higgs ◽  
Anna L. Olsen ◽  
Grant S. Stewart ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Damage Tolerance ◽  
Excision Repair ◽  
Replication Forks ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

AbstractPARP1 regulates the repair of DNA single strand breaks (SSBs) generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whilst PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication associated DNA damage due to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and through stabilising replication forks that encounter BER intermediates.

scholarly journals DNA breaks and chromosomal aberrations arise when replication meets base excision repair

2014 ◽  
Vol 206 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Michael Ensminger ◽  
Lucie Iloff ◽  
Christian Ebel ◽  
Teodora Nikolova ◽  
Bernd Kaina ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Chromosomal Aberrations ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Dna Breaks ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Base Excision

Exposures that methylate DNA potently induce DNA double-strand breaks (DSBs) and chromosomal aberrations, which are thought to arise when damaged bases block DNA replication. Here, we demonstrate that DNA methylation damage causes DSB formation when replication interferes with base excision repair (BER), the predominant pathway for repairing methylated bases. We show that cells defective in the N-methylpurine DNA glycosylase, which fail to remove N-methylpurines from DNA and do not initiate BER, display strongly reduced levels of methylation-induced DSBs and chromosomal aberrations compared with wild-type cells. Also, cells unable to generate single-strand breaks (SSBs) at apurinic/apyrimidinic sites do not form DSBs immediately after methylation damage. In contrast, cells deficient in x-ray cross-complementing protein 1, DNA polymerase β, or poly (ADP-ribose) polymerase 1 activity, all of which fail to seal SSBs induced at apurinic/apyrimidinic sites, exhibit strongly elevated levels of methylation-induced DSBs and chromosomal aberrations. We propose that DSBs and chromosomal aberrations after treatment with N-alkylators arise when replication forks collide with SSBs generated during BER.

scholarly journals Role of DNA base excision repair in the mutability and virulence of Streptococcus mutans

2012 ◽  
Vol 85 (2) ◽  
pp. 361-377 ◽  
Author(s):  
Kaisha Gonzalez ◽  
Roberta C. Faustoferri ◽  
Robert G. Quivey Jr
Keyword(s):  
Streptococcus Mutans ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision

scholarly journals Accumulation of true single strand breaks and AP sites in base excision repair deficient cells

2010 ◽  
Vol 694 (1-2) ◽  
pp. 65-71 ◽  
Author(s):  
April M. Luke ◽  
Paul D. Chastain ◽  
Brian F. Pachkowski ◽  
Valeriy Afonin ◽  
Shunichi Takeda ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Ap Sites ◽  
Base Excision

scholarly journals Base excision repair and its implications to cancer therapy

2020 ◽  
Vol 64 (5) ◽  
pp. 831-843 ◽  
Author(s):  
Gabrielle J. Grundy ◽  
Jason L. Parsons
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Process ◽  
Loss Of Function ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Base Excision ◽  
Integrity Of Dna

Abstract Base excision repair (BER) has evolved to preserve the integrity of DNA following cellular oxidative stress and in response to exogenous insults. The pathway is a coordinated, sequential process involving 30 proteins or more in which single strand breaks are generated as intermediates during the repair process. While deficiencies in BER activity can lead to high mutation rates and tumorigenesis, cancer cells often rely on increased BER activity to tolerate oxidative stress. Targeting BER has been an attractive strategy to overwhelm cancer cells with DNA damage, improve the efficacy of radiotherapy and/or chemotherapy, or form part of a lethal combination with a cancer specific mutation/loss of function. We provide an update on the progress of inhibitors to enzymes involved in BER, and some of the challenges faced with targeting the BER pathway.

scholarly journals The role of DNA base excision repair in brain homeostasis and disease

DNA Repair ◽  
2015 ◽  
Vol 32 ◽  
pp. 172-179 ◽  
Author(s):  
Mansour Akbari ◽  
Marya Morevati ◽  
Deborah Croteau ◽  
Vilhelm A. Bohr
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Base Excision Repair ◽  
Dna Base ◽  
Base Excision ◽  
Brain Homeostasis
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