scholarly journals Nonhomologous end-joining promotes resistance to DNA damage in the absence of an ADP-ribosyltransferase that signals DNA single strand breaks

2013 ◽  
Vol 126 (15) ◽  
pp. 3452-3461 ◽  
Author(s):  
C. A.-M. Couto ◽  
D.-W. Hsu ◽  
R. Teo ◽  
A. Rakhimova ◽  
S. Lempidaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Single Strand ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Adp Ribosyltransferase

scholarly journals PARP regulates nonhomologous end joining through retention of Ku at double-strand breaks

2011 ◽  
Vol 194 (3) ◽  
pp. 367-375 ◽  
Author(s):  
C. Anne-Marie Couto ◽  
Hong-Yu Wang ◽  
Joanna C.A. Green ◽  
Rhian Kiely ◽  
Robert Siddaway ◽  
...  
Keyword(s):  
Dna Damage ◽  
Adenosine Diphosphate ◽  
Early Response ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
Concomitant Increase ◽  
End Joining ◽  
Strand Breaks ◽  
Single Strand Breaks

Poly adenosine diphosphate (ADP)–ribosylation (PARylation) by poly ADP-ribose (PAR) polymerases (PARPs) is an early response to DNA double-strand breaks (DSBs). In this paper, we exploit Dictyostelium discoideum to uncover a novel role for PARylation in regulating nonhomologous end joining (NHEJ). PARylation occurred at single-strand breaks, and two PARPs, Adprt1b and Adprt2, were required for resistance to this kind of DNA damage. In contrast, although Adprt1b was dispensable for PARylation at DSBs, Adprt1a and, to a lesser extent, Adprt2 were required for this event. Disruption of adprt2 had a subtle impact on the ability of cells to perform NHEJ. However, disruption of adprt1a decreased the ability of cells to perform end joining with a concomitant increase in homologous recombination. PAR-dependent regulation of NHEJ was achieved through promoting recruitment and/or retention of Ku at DSBs. Furthermore, a PAR interaction motif in Ku70 was required for this regulation and efficient NHEJ. These data illustrate that PARylation at DSBs promotes NHEJ through recruitment or retention of repair factors at sites of DNA damage.

scholarly journals XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes

2011 ◽  
Vol 208 (11) ◽  
pp. 2209-2216 ◽  
Author(s):  
Huseyin Saribasak ◽  
Robert W. Maul ◽  
Zheng Cao ◽  
Rhonda L. McClure ◽  
William Yang ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Single Strand ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Variable Regions ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Switch Regions

Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer’s patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1+/− splenic B cells, the length of microhomology at the switch junctions decreased, suggesting that XRCC1 also participates in alternative nonhomologous end joining. Furthermore, Xrcc1+/− B cells had reduced Igh/c-myc translocations during CSR, supporting a role for XRCC1 in microhomology-mediated joining. Our results imply that AID-induced single-strand breaks in Igh variable and switch regions become substrates simultaneously for BER and mutagenesis pathways.

scholarly journals Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

2018 ◽  
Vol 19 (8) ◽  
pp. 2389 ◽  
Author(s):  
Md. Hossain ◽  
Yunfeng Lin ◽  
Shan Yan
Keyword(s):  
Dna Damage ◽  
Genome Instability ◽  
Strand Break ◽  
Single Strand ◽  
Genome Integrity ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response ◽  
End Resection

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

scholarly journals DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity

2012 ◽  
Vol 19 (11) ◽  
pp. 1741-1749 ◽  
Author(s):  
P Fortini ◽  
C Ferretti ◽  
B Pascucci ◽  
L Narciso ◽  
D Pajalunga ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Muscle Cells ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Damage Response

scholarly journals Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrea M. Kaminski ◽  
John M. Pryor ◽  
Dale A. Ramsden ◽  
Thomas A. Kunkel ◽  
Lars C. Pedersen ◽  
...  
Keyword(s):  
Chromosomal Rearrangements ◽  
Strand Break ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Template Strand ◽  
Single Strand Breaks ◽  
Dna Double Strand Break ◽  
Break Site

Abstract Genomic integrity is threatened by cytotoxic DNA double-strand breaks (DSBs), which must be resolved efficiently to prevent sequence loss, chromosomal rearrangements/translocations, or cell death. Polymerase μ (Polμ) participates in DSB repair via the nonhomologous end-joining (NHEJ) pathway, by filling small sequence gaps in broken ends to create substrates ultimately ligatable by DNA Ligase IV. Here we present structures of human Polμ engaging a DSB substrate. Synapsis is mediated solely by Polμ, facilitated by single-nucleotide homology at the break site, wherein both ends of the discontinuous template strand are stabilized by a hydrogen bonding network. The active site in the quaternary Pol μ complex is poised for catalysis and nucleotide incoporation proceeds in crystallo. These structures demonstrate that Polμ may address complementary DSB substrates during NHEJ in a manner indistinguishable from single-strand breaks.

scholarly journals Inactivation of Ku-Mediated End Joining Suppresses mec1Δ Lethality by Depleting the Ribonucleotide Reductase Inhibitor Sml1 through a Pathway Controlled by Tel1 Kinase and the Mre11 Complex

2005 ◽  
Vol 25 (23) ◽  
pp. 10652-10664 ◽  
Author(s):  
Yves Corda ◽  
Sang Eun Lee ◽  
Sylvine Guillot ◽  
André Walther ◽  
Julie Sollier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ribonucleotide Reductase ◽  
Reductase Inhibitor ◽  
Nonhomologous End Joining ◽  
Dna Damage Checkpoint ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Ribonucleotide Reductase Inhibitor ◽  
Kinase Cascade

ABSTRACT RAD53 and MEC1 are essential Saccharomyces cerevisiae genes required for the DNA replication and DNA damage checkpoint responses. Their lethality can be suppressed by increasing the intracellular pool of deoxynucleotide triphosphates. We report that deletion of YKU70 or YKU80 suppresses mec1Δ, but not rad53Δ, lethality. We show that suppression of mec1Δ lethality is not due to Ku−-associated telomeric defects but rather results from the inability of Ku− cells to efficiently repair DNA double strand breaks by nonhomologous end joining. Consistent with these results, mec1Δ lethality is also suppressed by lif1Δ, which like yku70Δ and yku80Δ, prevents nonhomologous end joining. The viability of yku70Δ mec1Δ and yku80Δ mec1Δ cells depends on the ATM-related Tel1 kinase, the Mre11-Rad50-Xrs2 complex, and the DNA damage checkpoint protein Rad9. We further report that this Mec1-independent pathway converges with the Rad53/Dun1-regulated checkpoint kinase cascade and leads to the degradation of the ribonucleotide reductase inhibitor Sml1.

scholarly journals A CAF-1–PCNA-Mediated Chromatin Assembly Pathway Triggered by Sensing DNA Damage

2000 ◽  
Vol 20 (4) ◽  
pp. 1206-1218 ◽  
Author(s):  
Jonathan G. Moggs ◽  
Paola Grandi ◽  
Jean-Pierre Quivy ◽  
Zophonías O. Jónsson ◽  
Ulrich Hübscher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Single Strand ◽  
Chromatin Assembly ◽  
Checkpoint Control ◽  
Free System ◽  
Strand Breaks ◽  
Assembly Pathway ◽  
Single Strand Breaks ◽  
Damaged Dna

ABSTRACT Sensing DNA damage is crucial for the maintenance of genomic integrity and cell cycle progression. The participation of chromatin in these events is becoming of increasing interest. We show that the presence of single-strand breaks and gaps, formed either directly or during DNA damage processing, can trigger the propagation of nucleosomal arrays. This nucleosome assembly pathway involves the histone chaperone chromatin assembly factor 1 (CAF-1). The largest subunit (p150) of this factor interacts directly with proliferating cell nuclear antigen (PCNA), and critical regions for this interaction on both proteins have been mapped. To isolate proteins specifically recruited during DNA repair, damaged DNA linked to magnetic beads was used. The binding of both PCNA and CAF-1 to this damaged DNA was dependent on the number of DNA lesions and required ATP. Chromatin assembly linked to the repair of single-strand breaks was disrupted by depletion of PCNA from a cell-free system. This defect was rescued by complementation with recombinant PCNA, arguing for role of PCNA in mediating chromatin assembly linked to DNA repair. We discuss the importance of the PCNA–CAF-1 interaction in the context of DNA damage processing and checkpoint control.

Methylated DNA Causes a Physical Block to Replication Forks Independently of Damage Signalling, O6-Methylguanine or DNA Single-Strand Breaks and Results in DNA Damage

2010 ◽  
Vol 402 (1) ◽  
pp. 70-82 ◽  
Author(s):  
Petra Groth ◽  
Simon Ausländer ◽  
Muntasir Mamun Majumder ◽  
Niklas Schultz ◽  
Fredrik Johansson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Single Strand ◽  
Replication Forks ◽  
Strand Breaks ◽  
Methylated Dna ◽  
Single Strand Breaks
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