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DePARylation's Role in S Phase Progression and Cell Survival

Core Concepts
DePARylation of S phase pADPr by PARG is essential for cell viability.
The content explores the critical role of dePARylation in regulating DNA damage response. It highlights how PARG-mediated dePARylation of S phase pADPr is crucial for cell survival, emphasizing the impact on Okazaki fragment ligation and base excision repair. The study also delves into the potential of PARG as a biomarker for cancer therapy involving PARG inhibitors. Abstract: PARP1 and PARG play vital roles in DNA damage response regulation. DePARylation by PARG is essential for cell viability. Loss of dePARylation activity leads to uncontrolled pADPr accumulation and cytotoxicity. Introduction: PARylation by PARP1 is crucial for DNA damage repair. PARG functions as a key dePARylation enzyme. Targeting dePARylation is considered to overcome PARP inhibitor resistance. Results: PARG depletion increases sensitivity to PARGi. Unligated Okazaki fragments induce S phase-specific pADPr signaling. Loss of genes involved in BER or Okazaki fragment ligation enhances sensitivity to PARGi. Data Extraction: Loss of full-length PARG expression correlates with increased sensitivity to PARG inhibition.
Loss of full-length PARG expression correlates with increased sensitivity to PARG inhibition.
"Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance." "PARG depletion leads to drastic sensitivity to PARGi."

Deeper Inquiries

How does unligated Okazaki fragments lead to S phase-specific pADPr signaling?

Unligated Okazaki fragments are short DNA sequences synthesized on the lagging strand during DNA replication. When these fragments are not properly ligated, they can activate PARP1, leading to the generation of endogenous S phase pADPr. This occurs because the maturation of Okazaki fragments involves single-strand nicks on DNA that may require PARP1-dependent recruitment of XRCC1 and LIG3 for ligation. The presence of unligated Okazaki fragments activates PARP1 in an attempt to repair this damage, resulting in the specific accumulation of pADPr signals in S phase cells.

What are the implications of targeting dePARylation in cancer therapy?

Targeting dePARylation, particularly through enzymes like PARG, presents a promising strategy in cancer therapy. Inhibiting dePARylation can lead to increased levels of pADPr and subsequent cytotoxicity due to disrupted DNA repair processes and NAD+ depletion. This approach is especially relevant for cancers with deficiencies in homologous recombination (HR) or other DNA damage response pathways as they exhibit increased sensitivity to PARG inhibitors (PARGi). By inhibiting dePARylation, it is possible to sensitize cancer cells to radiation therapy and chemotherapy while potentially overcoming resistance mechanisms associated with PARP inhibitors.

How does the loss of full-length PARG expression affect cellular responses to DNA damage?

The loss or inhibition of full-length PARG expression significantly impacts cellular responses to DNA damage. Cells lacking functional PARG activity show extreme sensitivity when exposed to PARG inhibitors (PARGi), leading to cytotoxic effects mediated by uncontrolled accumulation of poly(ADP-ribose) (pADPr). Additionally, reduced or absent full-length PARG expression results in prolonged chromatin-bound PARP1/2 complexes following DNA damage events, contributing further towards cell death due to disrupted NAD+ homeostasis and excessive activation of downstream pathways involved in apoptosis and cell cycle regulation. Furthermore, low levels or absence of full-length PARG expression serve as potential biomarkers for predicting sensitivity towards PAGRi-based therapies in various cancers where such alterations exist.