scholarly journals GLP-catalyzed H4K16me1 promotes 53BP1 recruitment to permit DNA damage repair and cell survival

2019 ◽  
Vol 47 (21) ◽  
pp. 10977-10993 ◽  
Author(s):  
Xiaopeng Lu ◽  
Ming Tang ◽  
Qian Zhu ◽  
Qiaoyan Yang ◽  
Zhiming Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Dna Damage Repair ◽  
Binding Activity ◽  
Critical Event ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Damage Repair ◽  
Underlying Mechanisms

Abstract The binding of p53-binding protein 1 (53BP1) to damaged chromatin is a critical event in non-homologous DNA end joining (NHEJ)-mediated DNA damage repair. Although several molecular pathways explaining how 53BP1 binds damaged chromatin have been described, the precise underlying mechanisms are still unclear. Here we report that a newly identified H4K16 monomethylation (H4K16me1) mark is involved in 53BP1 binding activity in the DNA damage response (DDR). During the DDR, H4K16me1 rapidly increases as a result of catalyzation by the histone methyltransferase G9a-like protein (GLP). H4K16me1 shows an increased interaction level with 53BP1, which is important for the timely recruitment of 53BP1 to DNA double-strand breaks. Differing from H4K16 acetylation, H4K16me1 enhances the 53BP1–H4K20me2 interaction at damaged chromatin. Consistently, GLP knockdown markedly attenuates 53BP1 foci formation, leading to impaired NHEJ-mediated repair and decreased cell survival. Together, these data support a novel axis of the DNA damage repair pathway based on H4K16me1 catalysis by GLP, which promotes 53BP1 recruitment to permit NHEJ-mediated DNA damage repair.

scholarly journals G9a coordinates with the RPA complex to promote DNA damage repair and cell survival

2017 ◽  
Vol 114 (30) ◽  
pp. E6054-E6063 ◽  
Author(s):  
Qiaoyan Yang ◽  
Qian Zhu ◽  
Xiaopeng Lu ◽  
Yipeng Du ◽  
Linlin Cao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Survival ◽  
Cancer Cells ◽  
Dna Damage Repair ◽  
Protein A ◽  
Dna Double Strand Breaks ◽  
Gene Suppression ◽  
Cancer Cell Growth ◽  
Strand Breaks ◽  
Damage Repair

Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs. This mechanism facilitates homologous recombination (HR) and cell survival. We confirmed the interaction between RPA and G9a to be critical for RPA foci formation and HR upon DNA damage. Collectively, our findings demonstrate a regulatory pathway based on CK2–G9a–RPA that permits HR in cancer cells and provide further rationale for the use of G9a inhibitors as a cancer therapeutic.

scholarly journals Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

2015 ◽  
Vol 112 (24) ◽  
pp. 7507-7512 ◽  
Author(s):  
Ozge Gursoy-Yuzugullu ◽  
Marina K. Ayrapetov ◽  
Brendan D. Price
Keyword(s):  
Dna Damage ◽  
Double Strand Breaks ◽  
Histone H4 ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Nucleosome Dynamics ◽  
Chromatin Template ◽  
End Resection

The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4–Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative nonhomologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair.

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 Integrated Stochastic Model of DNA Damage Repair by Non-homologous End Joining and p53/p21- Mediated Early Senescence Signalling

2015 ◽  
Vol 11 (5) ◽  
pp. e1004246 ◽  
Author(s):  
David W. P. Dolan ◽  
Anze Zupanic ◽  
Glyn Nelson ◽  
Philip Hall ◽  
Satomi Miwa ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stochastic Model ◽  
Dna Damage Repair ◽  
End Joining ◽  
Damage Repair ◽  
Non Homologous End Joining

scholarly journals SIRT6 is a DNA Double-Strand Break Sensor

2019 ◽  
Author(s):  
Lior Onn ◽  
Miguel Portillo ◽  
Stefan Ilic ◽  
Gal Cleitman ◽  
Daniel Stein ◽  
...  
Keyword(s):  
Dna Damage ◽  
Binding Capacity ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
The Road ◽  
Non Homologous End Joining

AbstractDNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.

scholarly journals Abstract 4155: USP11 regulates UV-induced DNA damage repair and cell survival associated with skin cancer

2018 ◽  
Author(s):  
Palak Shah ◽  
Lei Qiang ◽  
Seungwon Yang ◽  
Keyoumars Soltani ◽  
Yu-Ying He
Keyword(s):  
Dna Damage ◽  
Skin Cancer ◽  
Cell Survival ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals GLI1: A Therapeutic Target for Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Justin T. Avery ◽  
Ruowen Zhang ◽  
Rebecca J. Boohaker
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Hedgehog Signaling ◽  
Dna Damage Repair ◽  
Therapeutic Benefit ◽  
Direct Inhibition ◽  
Hallmarks Of Cancer ◽  
Diagnostic Biomarkers ◽  
Damage Repair ◽  
Underlying Mechanisms

GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation.

scholarly journals HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

2022 ◽  
Author(s):  
Tej Pandita ◽  
Vijay Kumari Charaka ◽  
Sharmistha Chakraborty ◽  
Chi-Lin Tsai ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Assembly Factor ◽  
Chromo Shadow Domain

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.

scholarly journals DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Gut ◽  
2020 ◽  
pp. gutjnl-2019-319984 ◽  
Author(s):  
Lukas Perkhofer ◽  
Johann Gout ◽  
Elodie Roger ◽  
Fernando Kude de Almeida ◽  
Carolina Baptista Simões ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Dna Double Strand Breaks ◽  
Dismal Prognosis ◽  
Damage Repair ◽  
Personalised Treatment

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.

scholarly journals Poly(ADP-ribosyl)ation mediates early phase histone eviction at DNA lesions

2020 ◽  
Vol 48 (6) ◽  
pp. 3001-3013 ◽  
Author(s):  
Guang Yang ◽  
Yibin Chen ◽  
Jiaxue Wu ◽  
Shih-Hsun Chen ◽  
Xiuhua Liu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Molecular Mechanism ◽  
Parp Inhibitor ◽  
Repair Process ◽  
Dna Lesions ◽  
Histone Chaperones ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Dna Lesion ◽  
Damage Repair

Abstract Nucleosomal histones are barriers to the DNA repair process particularly at DNA double-strand breaks (DSBs). However, the molecular mechanism by which these histone barriers are removed from the sites of DNA damage remains elusive. Here, we have generated a single specific inducible DSB in the cells and systematically examined the histone removal process at the DNA lesion. We found that histone removal occurred immediately following DNA damage and could extend up to a range of few kilobases from the lesion. To examine the molecular mechanism underlying DNA damage-induced histone removal, we screened histone modifications and found that histone ADP-ribosylation was associated with histone removal at DNA lesions. PARP inhibitor treatment suppressed the immediate histone eviction at DNA lesions. Moreover, we examined histone chaperones and found that the FACT complex recognized ADP-ribosylated histones and mediated the removal of histones in response to DNA damage. Taken together, our results reveal a pathway that regulates early histone barrier removal at DNA lesions. It may also explain the mechanism by which PARP inhibitor regulates early DNA damage repair.

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