scholarly journals AURKB/Ipl1 restarts replication forks to recover from replication stress.

2021 ◽  
Author(s):  
Erin Moran ◽  
Katherine E Pfister ◽  
Kizhakke Mattada Sathyan ◽  
Brianne Vignero ◽  
Daniel J Burke ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Dna Damage Response ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Aurora Kinase ◽  
S Phase ◽  
Replication Forks ◽  
Aurora Kinase B ◽  
Dna Damaging Agents ◽  
Damage Response

Aurora kinase B (AURKB in human, Ipl1 in S. cerevisiae) is a master regulator of mitosis and its dysregulation has been implicated in chromosome instability. AURKB accumulates in the nucleus in S-phase and is regulated by CHK1 but has not been implicated in in the DNA Damage Response (DDR). Here we show that AURKB has a conserved role to recover from replication stress and restart replication forks. Active AURKB is localized to replication forks after a prolonged arrest. CHK1 phosphorylation of AURKB induces activating phosphorylation of PLK1 and both Aurora and Plk1 are required to deactivate the DDR. Clinical trials with AURKB inhibitors are designed to target established roles for AURKB in mitosis. Our data suggest combinations of AURKB inhibitors and DNA damaging agents could be of therapeutic importance.

scholarly journals Brc1 Promotes the Focal Accumulation and SUMO Ligase Activity of Smc5-Smc6 during Replication Stress

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Martina Oravcová ◽  
Mariana C. Gadaleta ◽  
Minghua Nie ◽  
Michael C. Reubens ◽  
Oliver Limbo ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Genetic Instability ◽  
Genome Stability ◽  
Replication Stress ◽  
Dna Lesions ◽  
Replication Forks ◽  
Response Factors ◽  
Sumo Ligase ◽  
Damage Response ◽  
Key Factor

ABSTRACT As genetic instability drives disease or loss of cell fitness, cellular safeguards have evolved to protect the genome, especially during sensitive cell cycle phases, such as DNA replication. Fission yeast Brc1 has emerged as a key factor in promoting cell survival when replication forks are stalled or collapsed. Brc1 is a multi-BRCT protein that is structurally related to the budding yeast Rtt107 and human PTIP DNA damage response factors, but functional similarities appear limited. Brc1 is a dosage suppressor of a mutation in the essential Smc5-Smc6 genome stability complex and is thought to act in a bypass pathway. In this study, we reveal an unexpectedly intimate connection between Brc1 and Smc5-Smc6 function. Brc1 is required for the accumulation of the Smc5-Smc6 genome stability complex in foci during replication stress and for activation of the intrinsic SUMO ligase activity of the complex by collapsed replication forks. Moreover, we show that the chromatin association and SUMO ligase activity of Smc5-Smc6 require the Nse5-Nse6 heterodimer, explaining how this nonessential cofactor critically supports the DNA repair roles of Smc5-Smc6. We also found that Brc1 interacts with Nse5-Nse6, as well as gamma-H2A, so it can tether Smc5-Smc6 at replicative DNA lesions to promote survival.

scholarly journals MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Dharmendra Kumar Singh ◽  
Raj K. Pandita ◽  
Mayank Singh ◽  
Sharmistha Chakraborty ◽  
Shashank Hambarde ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Stress ◽  
Replication Forks ◽  
Loop Formation ◽  
Origin Firing ◽  
Damage Site ◽  
Replicative Stress ◽  
Damage Response ◽  
Stalled Replication Forks

ABSTRACT The human MOF (hMOF) protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation; however, its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted of MOF and under replicative stress induced by cisplatin, hydroxyurea, or camptothecin have reduced survival, a higher frequency of S-phase-specific chromosome damage, and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing. MOF interacted with PCNA, a key coordinator of replication and repair machinery at replication forks, and affected its ubiquitination and recruitment to the DNA damage site. Depletion of MOF, therefore, compromised the DNA damage repair response as evidenced by decreased Mre11, RPA70, Rad51, and PCNA focus formation, reduced DNA end resection, and decreased CHK1 phosphorylation in cells after exposure to hydroxyurea or cisplatin. These results support the argument that MOF plays an important role in suppressing replication stress induced by genotoxic agents at several stages during the DNA damage response.

scholarly journals Cell cycle inertia underlies a bifurcation in cell fates after DNA damage

2021 ◽  
Vol 7 (3) ◽  
pp. eabe3882
Author(s):  
Jenny F. Nathans ◽  
James A. Cornwell ◽  
Marwa M. Afifi ◽  
Debasish Paul ◽  
Steven D. Cappell
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Tracking ◽  
Time Lapse ◽  
S Phase ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cell Fates ◽  
Damage Response ◽  
Time Lapse Imaging

The G1-S checkpoint is thought to prevent cells with damaged DNA from entering S phase and replicating their DNA and efficiently arrests cells at the G1-S transition. Here, using time-lapse imaging and single-cell tracking, we instead find that DNA damage leads to highly variable and divergent fate outcomes. Contrary to the textbook model that cells arrest at the G1-S transition, cells triggering the DNA damage checkpoint in G1 phase route back to quiescence, and this cellular rerouting can be initiated at any point in G1 phase. Furthermore, we find that most of the cells receiving damage in G1 phase actually fail to arrest and proceed through the G1-S transition due to persistent cyclin-dependent kinase (CDK) activity in the interval between DNA damage and induction of the CDK inhibitor p21. These observations necessitate a revised model of DNA damage response in G1 phase and indicate that cells have a G1 checkpoint.

scholarly journals NKX3.1 contributes to S phase entry and regulates DNA damage response (DDR) in prostate cancer cell lines

2011 ◽  
Vol 414 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Burcu Erbaykent-Tepedelen ◽  
Besra Özmen ◽  
Lokman Varisli ◽  
Ceren Gonen-Korkmaz ◽  
Bilge Debelec-Butuner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Lines ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
Prostate Cancer Cell ◽  
S Phase ◽  
Prostate Cancer Cell Lines ◽  
Damage Response ◽  
Phase Entry

scholarly journals Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer

2020 ◽  
Vol 295 (50) ◽  
pp. 17169-17186
Author(s):  
Mysore S. Veena ◽  
Santanu Raychaudhuri ◽  
Saroj K. Basak ◽  
Natarajan Venkatesan ◽  
Parameet Kumar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Dna Damage ◽  
Cell Growth ◽  
Cell Lines ◽  
Cancer Cell ◽  
Dna Damage Response ◽  
S Phase ◽  
Cervical Cancer Cell ◽  
Damage Response

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3′ terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.

scholarly journals Everything in Moderation: Lessons Learned by Exploiting Moderate Replication Stress in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1320 ◽  
Author(s):  
Nazareth ◽  
Jones ◽  
Gabrielli
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Replication Stress ◽  
Cytotoxic Chemotherapy ◽  
Clinical Development ◽  
Lessons Learned ◽  
The Poor ◽  
Damage Response ◽  
Specific Vulnerability

The poor selectivity of standard cytotoxic chemotherapy regimens causes severe side-effects in patients and reduces the quality of life during treatment. Targeting cancer-specific vulnerabilities can improve response rates, increase overall survival and limit toxic side effects in patients. Oncogene-induced replication stress serves as a tumour specific vulnerability and rationale for the clinical development of inhibitors targeting the DNA damage response (DDR) kinases (CHK1, ATR, ATM and WEE1). CHK1 inhibitors (CHK1i) have served as the pilot compounds in this class and their efficacy in clinical trials as single agents has been disappointing. Initial attempts to combine CHK1i with chemotherapies agents that enhance replication stress (such as gemcitabine) were reported to be excessively toxic. More recently, it has emerged that combining CHK1i with subclinical doses of replication stress inducers is more effective, better tolerated and more compatible with immunotherapies. Here we focus on the lessons learned during the clinical development of CHK1i with the goal of improving the design of future clinical trials utilizing DDR inhibitors to target replication stress in cancer.

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