Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments

Liao, Hongwei; Ji, Fang; Helleday, Thomas; Ying, Songmin

doi:10.15252/embr.201846263

Cited by 145 publications

(126 citation statements)

References 202 publications

(431 reference statements)

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“…Cellular replication stress, dNTP depletion, or collision of replication forks with DNA lesions results in fork reversal or fork regression and chicken foot formation [11]. SMARCAL1 is recruited by RPA-bound ssDNA to the replication fork [12], while Poly(ADP-Ribose)-Polymerase 1 (PARP1) is involved in fork reversal [11]. The RPA-bound ssDNA segments at the paused replication fork lead to the activation of ATR, which phosphorylates CHK1.…”

mentioning

confidence: 99%

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

Meyer

Becker

Classen

et al. 2020

Cells

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Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination. Homologous recombination (HR) prevents genomic instability by repair and protection of replication. It is unclear whether genetic alterations actually lead to a repair defect or whether superior signaling pathways are of greater importance. Previous studies focused exclusively on the repair function of HR. Here, we show that the regulation of HR by the intra-S-phase damage response at the replication is of overriding importance. A damage response activated by Ataxia telangiectasia and Rad3 related-checkpoint kinase 1 (ATR-CHK1) can prevent replication stress and leads to resistance formation. CHK1 thus has a preferred role over HR in preventing replication stress in TNBC. The signaling cascade ATR-CHK1 can compensate for a double-strand break repair error and lead to resistance of HR-deficient tumors. Established methods for the identification of HR-deficient tumors for Poly(ADP-Ribose)-Polymerase 1 (PARP1) inhibitor therapies should be extended to include analysis of candidates for intra-S phase damage response.

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mentioning

confidence: 99%

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

Meyer

Becker

Classen

et al. 2020

Cells

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“…MOV10 and PURA are both LINE-1 repressors (Taylor et al, 2018;Warkocki et al, 2018). PARP1 is a multifunctional DDR protein that is involved in the response to stalled replication forks (Liao et al, 2018). Its up-regulation could be a response to LINE-1 associated replication fork stalling.…”

Section: In Ovarian Cancer Line-1 Expression Is Not Associated With Dmentioning

confidence: 99%

LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

McKerrow

Wang

Mita

et al. 2020

Preprint

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Retrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.

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“…When the stalled replication fork cannot be stabilized, fork then collapse into a double-strand break, which is the most lethal type of DNA damage [47]. In response to DSBs, the MRE11-RAD50-NBS1 (MRN) complex recruits ATM to damaged DNA sites and stimulates ATM kinase activity [48].…”

Section: Dna Rsr and Dsb Repairmentioning

confidence: 99%

“…In recent years, exacerbating replication stress seems to be a powerful means to kill cancer cells through mitotic catastrophe due to intolerable levels of replication stress [46]. In dealing with high levels of endogenous or exogenous replication stress, SCLC cells have acquired an intricate genome-protective mechanism to counteract high levels of replication stress during the long history of cellular evolution [47]. Transcriptomic profiling analysis uncovered that a number of genes involved in replication fork stabilization are overexpressed in SCLC cells, which might mediate replication stress tolerance [58].…”

Section: The Rationales For Enhancing Replication Catastrophe In Sclcmentioning

confidence: 99%

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Bian

Lin

2019

Cancers

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Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

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Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments

Cited by 145 publications

References 202 publications

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

Prevention of DNA Replication Stress by CHK1 Leads to Chemoresistance Despite a DNA Repair Defect in Homologous Recombination in Breast Cancer

LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

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