CARM1 regulates replication fork speed and stress response by stimulating PARP1

Genois, Marie-Michelle; Gagné, Jean-Philippe; Yasuhara, Takaaki; Jackson, Jessica; Saxena, Sneha; Langelier, Marie-France; Ahel, Ivan; Bedford, Mark T.; Pascal, John M.; Vindigni, Alessandro; Poirier, Guy G.; Zou, Lee

doi:10.1016/j.molcel.2020.12.010

Cited by 74 publications

(56 citation statements)

References 71 publications

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“…The copyright holder for this preprint this version posted May 19, 2021. ; https://doi.org/10.1101/2021.05.18.444697 doi: bioRxiv preprint employed distinct FDA-approved PARP inhibitors, Veliparib and Talazoparib, which have different potency and affect fork speed with different magnitude (Genois et al, 2021;Murai et al, 2013Murai et al, , 2014. Consistent with the results obtained with Olaparib (Figure 2F), we also observed suppression of cATRi-induced fork slowing with both Veliparib and Talazoparib (Figure 3A).…”

Section: Suppression Of Fork Slowing By Parp Inhibitors Correlates With Catri/parpi Toxicitysupporting

confidence: 84%

“…Consistent with the results obtained with Olaparib (Figure 2F), we also observed suppression of cATRi-induced fork slowing with both Veliparib and Talazoparib (Figure 3A). The extent of fork speeding was correlated with the potency of the PARPi used, being higher for Talazoparib and lower with Veliparib (Genois et al, 2021;Murai et al, 2013Murai et al, , 2014. In line with the idea that fork reversal and fork slowing following cATRi is a key adaptive response protecting genome integrity, fork speed suppression by PARP inhibition resulted in a marked toxicity over a 5-day ATRi/PARPi co-treatment in U-2OS and HCT116 cells (Figures 3B, C).…”

Section: Suppression Of Fork Slowing By Parp Inhibitors Correlates With Catri/parpi Toxicitysupporting

confidence: 68%

“…The rather frequent events of fork reversal observed following cATRi indicate that the equilibrium between fork regression and restoration is shifted towards the regressed state possibly due to the impairment of fork restart or lesion-bypass mechanisms. Indeed, cATRi may affect PRIMPOL stabilization and PRIMPOL-mediated repriming (Bai et al, 2020;Genois et al, 2021;Quinet et al, 2020) and could also affect the DNA2/WRN-mediated restart pathway, given the ATR requirement for WRN localization to stalled forks (Ammazzalorso et al, 2010).…”

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confidence: 99%

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Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

Dibitetto

Sanchi

Sanford

et al. 2021

Preprint

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Inhibitors of the replication stress response kinase ATR are currently being explored in anti-cancer therapy. Acute ATR inhibition is known to impair the proper control of origin firing, DNA repair, and cell cycle, resulting in DNA breaks and mitotic catastrophe. Less is understood about the effects of clinically relevant regimes of ATR inhibition, which involve chronic and low doses of ATR inhibitors (cATRi) to cells. Here we report distinctive molecular effects of cATRi on replication dynamics. cATRi strongly reduces fork speed but has minimal effects on the accumulation of DNA breaks or cell survival. cATRi promotes extensive fork reversal and RAD51- and PARP-mediated fork slowing that correlate with the accumulation of DNA-RNA hybrids. Our work shows that fork reversal is a critical adaptive response ensuring cell survival during cATRi and that the manipulation of fork reversal causes hypersensitivity to cATRi, increasing the effectiveness of ATR inhibitors in anti-cancer therapies.

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Section: Suppression Of Fork Slowing By Parp Inhibitors Correlates With Catri/parpi Toxicitysupporting

confidence: 84%

Section: Suppression Of Fork Slowing By Parp Inhibitors Correlates With Catri/parpi Toxicitysupporting

confidence: 68%

mentioning

confidence: 99%

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Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

Dibitetto

Sanchi

Sanford

et al. 2021

Preprint

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“…Interestingly, we observed that treatment with both APR-246 and CX-5461 led to acceleration of the fork speed in SUM159PT cells, which is further exacerbated upon combination treatment. Accelerated fork elongation is proven to be a mechanism for replication stress and DNA damage as demonstrated by several recent studies on PARP inhibitors [54,55]. Thus, our data demonstrate that both APR-246 and CX-5461 cause replication stress, possibly via similar effects but to varying extents, on fork progression.…”

Section: Discussionsupporting

confidence: 73%

CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

Makhale

Nanayakkara

Raninga

et al. 2021

IJMS

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

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“…However, if HLTF is present and allowed to bind to the replication fork but contains an inactive HIRAN domain (the domain that binds the 3′-hydroxyl group of nascent DNA), PrimPol is outcompeted at the fork and does not act, and the role of S phase progression is undertaken by Rev1. Similar work has shown that in the absence of CARM1, a protein implicated in the stabilisation of reversed forks, PrimPol and TLS are both employed in restarting replication forks ( 159 ). The balance between these complementary DTT pathways therefore has the potential to mask the key roles that repriming undertakes in vivo .…”

Section: Introduction: the Eukaryotic Dna Replication Machinerymentioning

confidence: 86%

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

Bainbridge

Teague

Doherty

2021

Nucleic Acids Research

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To bypass a diverse range of fork stalling impediments encountered during genome replication, cells possess a variety of DNA damage tolerance (DDT) mechanisms including translesion synthesis, template switching, and fork reversal. These pathways function to bypass obstacles and allow efficient DNA synthesis to be maintained. In addition, lagging strand obstacles can also be circumvented by downstream priming during Okazaki fragment generation, leaving gaps to be filled post-replication. Whether repriming occurs on the leading strand has been intensely debated over the past half-century. Early studies indicated that both DNA strands were synthesised discontinuously. Although later studies suggested that leading strand synthesis was continuous, leading to the preferred semi-discontinuous replication model. However, more recently it has been established that replicative primases can perform leading strand repriming in prokaryotes. An analogous fork restart mechanism has also been identified in most eukaryotes, which possess a specialist primase called PrimPol that conducts repriming downstream of stalling lesions and structures. PrimPol also plays a more general role in maintaining efficient fork progression. Here, we review and discuss the historical evidence and recent discoveries that substantiate repriming as an intrinsic replication restart pathway for maintaining efficient genome duplication across all domains of life.

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CARM1 regulates replication fork speed and stress response by stimulating PARP1

Cited by 74 publications

References 71 publications

Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

Repriming DNA synthesis: an intrinsic restart pathway that maintains efficient genome replication

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