DNA-PKcs promotes fork reversal and chemoresistance

Dibitetto, Diego; Marshall, Shannon; Sanchi, Andrea; Liptay, Martin; Badar, Jumana; Lopes, Massimo; Rottenberg, Sven; Smolka, Marcus B.

doi:10.1016/j.molcel.2022.08.028

Cited by 25 publications

(23 citation statements)

References 50 publications

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“…On the other hand, it has been reported that replication fork stability confers PARP inhibitor resistance 20,34 . Our data from ZNF251KD cells is consistent with that and mechanistically in concordance with the nding that DNA-PKcs activity is required for this effect 25 .…”

Section: Discussionsupporting

confidence: 91%

“…ZNF251 haploinsu ciency increases DNA-PKcs-dependent replication fork protection in olaparib-treated BRCA1-mutated cells It has been reported that resistance to PARPis induced synthetic lethality might result not only from enhanced DSB repair, but also from enhanced fork stabilization 24 . Intriguingly, DNA-PKcs, independently of its role in D-NHEJ, promoted resistance to PARPi which was associated with fork protection (fork slowing and reversal) 25 . Thus, to further explore the molecular mechanism underlying ZNF251 haploinsu ciency -caused olaparib resistance, we test whether DNA-PKcs inhibitor (PIK-75) affected stabilization of DNA replication fork.…”

Section: Znf251 Haploinsu Ciency Increases Nhej Repairmentioning

confidence: 99%

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Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells

Chatla

Vekariya³

et al. 2023

Preprint

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Poly (ADP-ribose) polymerase (PARP) inhibitors represent a promising new class of agents that have demonstrated efficacy in treating various cancers, particularly those that carry BRCA1/2 mutations. The cancer associated BRCA1/2 mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPis) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, resistance to PARPis is common and can occur through multiple mechanisms, including the restoration of HR and/or the stabilization of replication forks. To gain a better understanding of the mechanisms underlying PARPi resistance, we conducted an unbiased CRISPR-pooled genome-wide library screen to identify new genes whose deficiency confers resistance to the PARPi olaparib. Our study revealed that ZNF251, a transcription factor, is a novel gene whose haploinsufficiency confers PARPi resistance in multiple breast and ovarian cancer lines harboring BRCA1 mutations. Mechanistically, we discovered that ZNF251 haploinsufficiency leads to constitutive stimulation of DNA-PKcs-dependent non-homologous end joining (NHEJ) repair of DSBs and DNA-PKcs-mediated fork protection in BRCA1-mutated cancer cells (BRCA1mut + ZNF251KD). Moreover, we demonstrated that DNA-PKcs inhibitors can restore PARPi sensitivity in BRCA1mut + ZNF251KD cells ex vivo and in vivo. Our findings provide important insights into the mechanisms underlying PARPi resistance and highlight the unexpected role of DNA-PKcs in this phenomenon.

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Section: Discussionsupporting

confidence: 91%

Section: Znf251 Haploinsu Ciency Increases Nhej Repairmentioning

confidence: 99%

Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells

Chatla

Vekariya³

et al. 2023

Preprint

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“…Recently, the Moldovan's lab demonstrated that human KU association to HU-stalled fork depends on fork reversal at which the KU-PARP14 axis is part of a multistep process to regulate nascent strand degradation 60 . In contrast, the Smolka's lab showed that KU-DNAPK stabilizes HU-stalled fork by promoting fork reversal and subsequent nascent strand degradation 74 . While these reports underscore the importance of regulating NHEJmediated fork protection pathways, they also suggest that human KU may act at multiple steps during fork-protection.…”

Section: Discussionmentioning

confidence: 94%

RNA:DNA hybrids from Okazaki fragments contribute to establish the Ku-mediated barrier to replication-fork degradation

Audoynaud¹,

Schirmeisen²,

Saada³

et al. 2023

Molecular Cell

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“…Additionally, DNA2, which functions in dsDNA break repair, has been shown to assist Werner syndrome helicase WRN in controlling HR-mediated restart of reversed replication forks [ 36 , 37 ]. Recently, Dibitetto et al identified the essential role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in promoting fork reversal and preventing genome instability [ 38 ]. They found that DNA-PKcs inhibition in BRCA2-deficient breast cancer with acquired PARPi resistance efficiently restored drug sensitivity by impairing fork slowing.…”

Section: Mechanisms Of the Cellular Response To Replication Stress An...mentioning

confidence: 99%

Exploiting DNA Replication Stress as a Therapeutic Strategy for Breast Cancer

2022

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Proliferating cells rely on DNA replication to ensure accurate genome duplication. Cancer cells, including breast cancer cells, exhibit elevated replication stress (RS) due to the uncontrolled oncogenic activation, loss of key tumor suppressors, and defects in the DNA repair machinery. This intrinsic vulnerability provides a great opportunity for therapeutic exploitation. An increasing number of drug candidates targeting RS in breast cancer are demonstrating promising efficacy in preclinical and early clinical trials. However, unresolved challenges lie in balancing the toxicity of these drugs while maintaining clinical efficacy. Furthermore, biomarkers of RS are urgently required to guide patient selection. In this review, we introduce the concept of targeting RS, detail the current therapies that target RS, and highlight the integration of RS with immunotherapies for breast cancer treatment. Additionally, we discuss the potential biomarkers to optimizing the efficacy of these therapies. Together, the continuous advances in our knowledge of targeting RS would benefit more patients with breast cancer.

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DNA-PKcs promotes fork reversal and chemoresistance

Cited by 25 publications

References 50 publications

Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells

Haploinsufficiency of ZNF251 causes DNA-PKcs-dependent resistance to PARP inhibitors in BRCA1-mutated cancer cells

RNA:DNA hybrids from Okazaki fragments contribute to establish the Ku-mediated barrier to replication-fork degradation

Exploiting DNA Replication Stress as a Therapeutic Strategy for Breast Cancer

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