Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation

Zhang, Chuanchao; Zhou, Bo; Gu, Feng; Liu, Hongmei; Wu, Honglin; Yao, Feng; Zheng, Hui; Fu, Hui; Chong, Wei; Cai, Shurui; Huang, Min; Ma, Xinwen; Guo, Zhifang; Li, Tingting; Deng, Wei; Zheng, Meiwen; Qiao, Junfei; Zhao, Yongliang; Ma, Yongjie; Wang, Qi-En; Tang, Tie-Shan; Guo, Caixia

doi:10.1016/j.molcel.2022.01.020

Cited by 36 publications

(29 citation statements)

References 67 publications

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“…The microirradiation was carried with a pulsed nitrogen laser (365 nm, 10-Hz pulse) as previously described ( 42 , 43 , 44 ). Briefly, U2OS cells were seeded on 35-mm glass bottom dishes (MatTek) overnight before transfection with GFP-Pol η.…”

Section: Methodsmentioning

confidence: 99%

DNA polymerase η promotes nonhomologous end joining upon etoposide exposure dependent on the scaffolding protein Kap1

Wang

Zhou

et al. 2022

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

DNA polymerase η promotes nonhomologous end joining upon etoposide exposure dependent on the scaffolding protein Kap1

Wang

Zhou

et al. 2022

Journal of Biological Chemistry

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“…HMGB3 is a novel interactor of PARP1 that can stimulate the PARylation activity of PARP1 and inhibit PARP trapping, resulting in olaparib resistance in ovarian cancer (Ma et al, 2022). A recent study by Zhang and colleagues found that PACMP, a lncRNAderived micropeptide, is an activator that promotes PARP1meidiated PARylation, and PACMP inhibition renders sensitivity of cancer cells to diverse chemo-and targeted therapies (Zhang et al, 2022). SPINDOC is a component of the histone-code effector protein complex SPIN1.…”

Section: Positive Regulators Of Parp1 Catalytic Activitymentioning

confidence: 99%

Human PARP1 substrates and regulators of its catalytic activity: An updated overview

et al. 2023

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Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that is recruited to damaged sites after DNA strand breaks to initiate DNA repair. This is achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD+, on the amino acid residues of itself or other acceptor proteins. PARP inhibitors (PARPi) that inhibit PARP catalytic activity and induce PARP trapping are commonly used for treating BRCA1/2-deficient breast and ovarian cancers through synergistic lethality. Unfortunately, resistance to PARPi frequently occurs. In this review, we present the novel substrates and regulators of the PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) that have been identified in the last 3 years. The overall aim is the presentation of protein interactions of potential therapeutic intervention for overcoming the resistance to PARPi.

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“…CtIP is also a target of a lncRNA (lnc15.2)-encoded micropeptide termed PACMP. PACMP stabilizes CtIP by blocking its ubiquitination, and it also promotes poly(ADP)ribosylation of substrates by PARP1 [ 130 ]. siRNA knockdown of lnc15.2 causes hypersensitivity to PARP1i, ATRi, CDK4/6i, the TopoI inhibitor camptothecin, the TopoII inhibitor epirubicin, and radiation, and it has antitumor activity against breast tumor xenografts [ 130 ].…”

Section: Targeting Replication Stress Signaling and Fork Repair/resta...mentioning

confidence: 99%

“…PACMP stabilizes CtIP by blocking its ubiquitination, and it also promotes poly(ADP)ribosylation of substrates by PARP1 [ 130 ]. siRNA knockdown of lnc15.2 causes hypersensitivity to PARP1i, ATRi, CDK4/6i, the TopoI inhibitor camptothecin, the TopoII inhibitor epirubicin, and radiation, and it has antitumor activity against breast tumor xenografts [ 130 ]. Together, these results warrant studies to further test the antitumor effects of CtIPi in preclinical and clinical trials.…”

Section: Targeting Replication Stress Signaling and Fork Repair/resta...mentioning

confidence: 99%

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

Nickoloff

2022

Molecules

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Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.

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Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation

Cited by 36 publications

References 67 publications

DNA polymerase η promotes nonhomologous end joining upon etoposide exposure dependent on the scaffolding protein Kap1

DNA polymerase η promotes nonhomologous end joining upon etoposide exposure dependent on the scaffolding protein Kap1

Human PARP1 substrates and regulators of its catalytic activity: An updated overview

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

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